Flap modulators

ABSTRACT

The present invention relates to compounds of Formula (I), 
                         
or a form thereof, wherein ring A, R 1 , R 2 , R 3 , R 3 ′, L, W, and V are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/760,627, filed Feb. 4, 2013, and U.S. Provisional Application No.61/800,353, filed Mar. 15, 2013, each of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to substituted compounds useful as5-lipoxygenase-activating protein (FLAP) modulators, pharmaceuticalcompositions of such compounds, methods of preparation and use thereof.More particularly, FLAP modulators are useful for preventing, treatingor ameliorating FLAP-mediated diseases and/or disorders, including thoseinflammation diseases and/or disorders associated with dermatologicaland respiratory disorders, allergic disorders, autoimmunity, cancer,cardiovascular and metabolic disorders.

BACKGROUND OF THE INVENTION

FLAP is a key initiator of the leukotriene synthesis pathway that bindsand then transfers arachidonic acid to 5-lipoxygenase (M. Abramovitz etal., “5-lipoxygenase-activating protein stimulates the utilization ofarachidonic acid by 5-lipoxygenase,” Eur. J. Biochem., 1993, 215,105-11). FLAP has been demonstrated to interact with LTC₄ synthase, andcould putatively modulate the production of LTC₄ (T. Strid et al.,“Distinct parts of leukotriene C(4) synthase interact with5-lipoxygenase and 5-lipoxygenase activating protein,” Biochem. Biophys.Res. Comm., 2009, 381(4), 518-22). Modulation (including withoutlimitation inhibition) or genetic deletion of FLAP blocks leukotrieneproduction, specifically LTB₄, the cysteinyl leukotrienes (LTC₄, LTD₄and LTE₄) as well as 5-oxo-ETE (J. Z. Haeggström et al., “Lipoxygenaseand leukotriene pathways: biochemistry, biology, and roles in disease,”Chem. Rev., 2011, 111(10), 5866-98).

Leukotrienes are immune-modulating lipids formed from arachidonic acid(reviewed in Samuelsson, “Leukotrienes: mediators of immediatehypersensitivity reactions and inflammation,” Science, 1983, 220,568-75). They are synthesized primarily by eosinophils, neutrophils,mast cells, basophils, dendritic cells, macrophages and monocytes.Leukotrienes mediate multiple biological effects including, by way ofexample only, smooth muscle contraction, leukocyte recruitment andactivation, cytokine secretion, fibrosis, mucous secretion, and vascularfunction (J. Z. Haeggström, at 5866-98).

FLAP-deficient mice are healthy and reproduce normally. They do notproduce leukotrienes and have decreased susceptibility in mouse modelsof arthritis (R. J. Griffiths et al., “Collagen-induced arthritis isreduced in 5-lipoxygenase-activating protein-deficient mice,” J. Exp.Med., 1997, 185, 1123-29). In humans, FLAP itself has been linked bygenetic studies to respiratory disorders and cardiovascular disease,including myocardial infarction, atherosclerosis and stroke (A.Helgadottir et al., “The gene encoding 5-lipoxygenase activating proteinconfers risk of myocardial infarction, atherosclerosis and stroke,” Nat.Genet., 2004, 36, 233-39; A. S. Tulah et al., “The role of ALOX5AP,LTA4H and LTB4R polymorphisms in determining baseline lung function andCOPD susceptibility in UK smokers,” BMC Med. Genet., 2011, 29(12), 173;R. Ji et al., “Genetic variants in the promoter region of the ALOX5APgene and susceptibility of ischemic stroke,” Cerebrovasc. Dis., 2011,32(3), 261-68; J. W. Holloway et al., “The role of LTA4H and ALOX5APpolymorphism in asthma and allergy susceptibility,” Allergy, 2008,63(8), 1046-53). In addition, studies using animal models support acausative role for leukotrienes in aortic aneurisms, atherosclerosis,myocardial infarction, atherosclerosis, and stroke (reviewed in J. Z.Haeggström, at 5866-98).

Leukotrienes also play a role in autoimmune disorders such as rheumatoidarthritis, inflammatory bowel disease, nephritis, spondyloarthritis,polymyositis, dermatomyositis, gouty effusions, systemic lupuserythematosus, systemic sclerosis, Alzheimer's disease and multiplesclerosis (S. Chwieśko-Minarowska et al., “The role of leukotrienes inthe pathogenesis of systemic sclerosis,” Folia Histochem. Cytobiol.,2012, 50(2), 180-85; M. Rosnowska et al., “Leukotrienes C4 and B4 incerebrospinal fluid of patients with multiple sclerosis,” Pol.Merkuriusz Lek., 1997, 2, 254-55; and reviewed in J. Z. Haeggström, at5866-98; I. Loell et al., “Activated LTB4 pathway in muscle tissue ofpatients with polymyositis or dermatomyositis,” Ann. Rheum. Dis., 2013,72(2), 293-99; J. Chu et al., “Involvement of 5-lipoxygenase activatingprotein in the amyloidotic phenotype of an Alzheimer's disease mousemodel,” J. Neuroinflammation, 2012, 9, 127). Leukotrienes have also beenimplicated in several aspects of carcinogenesis including tumor cellproliferation, differentiation, and apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells(D. Wang and R. N. Dubois, “Eicosanoids and cancer,” Nat. Rev. Cancer,2010, 10(3), 181-93).

Leukotrienes play a key role in allergic disorders such as allergicrhinitis, allergic dermatitis and asthma, as well as respiratorydisorders such as exacerbations, non-allergic asthma, fibrotic lungdiseases, acute respiratory distress syndrome and chronic obstructivepulmonary disease (reviewed in J. Z. Haeggström at 5866-98). Approvedantagonists of the LTC₄ receptor and leukotriene synthesis modulatorssuch as zileuton have shown clinical efficacy in a variety ofrespiratory disorders (reviewed in M. E. Krawiec and S. E. Wenzel,“Leukotriene modulators and non-steroidal therapies in the treatment ofasthma,” Expert. Opin. Pharmacotherapy, 2001, 2(1), 47-65).

All the above evidence supports a key role of leukotrienes in a varietyof human diseases and/or disorders, and FLAP modulation would beeffective for the prevention, treatment, or amelioration of theseimmune-mediated inflammatory diseases and/or disorders. Furthermore,there still remains a need for FLAP modulator compounds that havepharmacokinetic and pharmacodynamic properties suitable for use as humanpharmaceuticals.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compoundsuseful as, for example, FLAP modulators (including without limitationnovel compounds that inhibit FLAP), methods of preparing such compounds,pharmaceutical compositions comprising one or more such compounds,methods of preparing pharmaceutical compositions comprising one or moresuch compounds, and methods of prophylaxis, treatment, amelioration,including without limitation inhibition, of one or more diseases and/ordisorders associated with FLAP using such compounds or pharmaceuticalcompositions.

One aspect of the present invention is directed to compounds, methods,and compositions for the treatment or prophylaxis or amelioration of avariety of diseases and/or disorders that are mediated or sustainedthrough the activity of leukotrienes, including pulmonary, allergic,fibrotic, neurological, inflammatory, autoimmune and cardiovasculardiseases and cancer or associated symptoms or complications thereof.More specifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, fibrotic lung diseases, acuterespiratory distress syndrome and chronic obstructive pulmonary disease,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Another aspect of the present invention is directed to compounds,methods, and compositions for the treatment or prophylaxis oramelioration of cardiac and cardiovascular diseases and/or disorders, orassociated symptoms or complications thereof, that include but are notlimited to myocardial infarction, atherosclerosis and stroke aorticaneurisms, atherosclerosis, or associated symptoms or complicationsthereof, in a subject afflicted with such a disease and/or disorder,wherein the method comprises administering a FLAP modulator.

Yet another aspect of the present invention is directed to compounds,methods, and compositions for the prophylaxis, treatment, oramelioration of autoimmune diseases and/or disorders, or associatedsymptoms or complications thereof, that include but are not limited torheumatoid arthritis, inflammatory bowel disease, nephritis,spondyloarthritis, polymyositis, dermatomyositis, gouty effusions,systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease,multiple sclerosis or allergic disorders that include but are notlimited to allergic rhinitis, allergic dermatitis and asthma, orassociated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Finally, one aspect of the present invention is directed to compounds,methods, and compositions for the prophylaxis, treatment, oramelioration of carcinogenesis including but not limited to tumor cellproliferation, differentiation, and apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Another aspect of the present invention features a compound of Formula(I)

wherein

-   -   L is a bond, —CH₂—, —SO₂—, —CH₂—SO₂—, —SO₂—CH₂—, —SO₂—NR—,        —SO₂—NR—CH₂—, —CH₂—SO₂—NR—, —NR—, —NR—SO₂—, —S—, —S—CH₂—,        —CH₂—S—, —C(═O)—, —O—, —O—CH₂—, —NR—C(═O)—, or —C(═O)—NR—,        wherein R is H, C₁₋₂alkyl, C₁₋₂alkyl-OH or cyclopropyl;    -   R₁ is H, halo, methyl, CF₃, —O—CF₃, or —O—CH₃;    -   R₂ is H, cyano, halo, 2-(trimethylsilyl)ethoxy, phenyl,        C₁₋₆alkyl, heteroaryl, heterocyclyl, C₃₋₉cycloalkyl, provided R₂        is not H if L is a bond, and wherein said phenyl, C₁₋₆alkyl,        heteroaryl, heterocyclyl or C₃₋₉cycloalkyl is optionally and        independently substituted selected from the group consisting of:    -   methyl, ethyl, oxo, fluoro, hydroxyl, cyano, amino, methoxy,        tert-butoxy, acetyl, cyclopropyl, cyclobutyl, cyclohexyl,        phenyl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl,        2,4-dihydro-3H-1,2,4-triazol-3-one-4-yl, 1H-imidazol-4-yl,        pyrazin-2-yl, pyrimidin-2-yl, 1,3-oxazolidin-2-one-5-yl,        N-benzamide, 4-methylpiperazin-1-yl, morpholin-4-yl, CF₃,        —SO₂—CH₃, —C(═O)-cyclopropyl, —NHCH₃, —N(CH₃)₂, —NHAc,        —NHCO₂t-Bu, —CH₂—NH₂, —C(═O)—NH₂, —C(═O)—N(ethyl)₂,        —NH—C(═O)—NH₂, —NH—C(═O)—CH₃, —C(═O)—(C₁-C₄alkyl), —C(═O)—OH,        —C(═O)—NH(C₁-C₄alkyl), —(CH₂)_(n)—OH, and —(CH₂)_(n)—CN, wherein        n is 1 or 2;    -   V is CH, CR′, or N, wherein R′ is methyl or F;    -   W is CR″ or N, wherein R″ is H, F, hydroxyl, amino, CH₃ or        —O—CH₃;    -   ring A is selected from the group consisting of:

-   -   R₃ is H, F, methyl, or —O—CH₃;    -   R₃′ is H or F;    -   R₄ is H, methyl, cyano, amino, halo, —COOH, or —O—CH₃;    -   R₅ is H, methyl, cyano, or —CF₃;    -   R₆ is H, cyano, amino, halo, or —CF₃; and    -   R₇ is halo, amino, —CONH₂, cyano, —O—CH₃, —CF₃, or —COO-ethyl;

or an optical isomer, hydrate, metabolite, enantiomer, diastereomer,cis-trans isomer, racemate, prodrug or pharmaceutically acceptable saltthereof.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier. The invention is also directedtowards providing a process for formulating a pharmaceuticalcomposition, comprising formulating a pharmaceutical composition of atleast one compound of Formula (I) and at lease one pharmaceuticallyacceptable carrier. The present invention further relates to a processfor making a pharmaceutical composition comprising mixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease and/or disorder mediated byFLAP activity, comprising administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I). Such a diseaseand/or disorder can include, but is not limited to respiratorydisorders, cardiac and cardiovascular diseases, autoimmune disorders,carcinogenesis or associated symptoms or complications. Morespecifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, fibrotic lung diseases, acuterespiratory distress syndrome, chronic obstructive pulmonary diseasemyocardial infarction, atherosclerosis and stroke aortic aneurisms,atherosclerosis, rheumatoid arthritis, inflammatory bowel disease,nephritis, spondyloarthritis, polymyositis, dermatomyositis, goutyeffusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer'sdisease, multiple sclerosis, allergic rhinitis, allergic dermatitis andasthma, tumor cell proliferation, differentiation, and apoptosis,tumor-associated angiogenesis, as well as the migration and invasion ofcarcinoma cells, or associated symptoms or complications thereof, in asubject afflicted with such a disease and/or disorder, or associatedsymptoms or complications thereof, wherein the method comprisesadministering a FLAP modulator to a subject in need thereof, atherapeutically effective amound of at least one compound of Formula(I), preferably in a pharmaceutical composition comprising at least onecompound of Formula (I).

Additional embodiments and advantages of the invention will becomeapparent from the detailed discussion, schemes, examples, and claimsbelow.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel FLAP modulators and compositions thereoffor the prophylaxis, treatment, or amelioration of numerous diseasesand/or disorders, including but not limited to respiratory diseasesand/or disorders, cardiac and cardiovascular diseases and/or disorders,autoimmune diseases and/or disorders, carcinogenesis, and associatedsymptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

-   -   L is a bond, —CH₂—, —SO₂—, —CH₂—SO₂—, —SO₂—CH₂—, —SO₂—NR—,        —SO₂—NR—CH₂—, —CH₂—SO₂—NR—, —NR—, —NR—SO₂—, —S—, —S—CH₂—,        —CH₂—S—, —C(═O)—, —O—, —O—CH₂—, —NR—C(═O)—, or —C(═O)—NR—,        wherein R is H, C₁₋₂alkyl, C₁₋₂alkyl-OH or cyclopropyl;    -   R₁ is H, halo, methyl, CF₃, —O—CF₃, or —O—CH₃;    -   R₂ is H, cyano, halo, 2-(trimethylsilyl)ethoxy, phenyl,        C₁₋₆alkyl, heteroaryl, heterocyclyl, C₃₋₉cycloalkyl, provided R₂        is not H if L is a bond, and wherein said phenyl, C₁₋₆alkyl,        heteroaryl, heterocyclyl or C₃₋₉cycloalkyl is optionally and        independently substituted selected from the group consisting of:    -   methyl, ethyl, oxo, fluoro, hydroxyl, cyano, amino, methoxy,        tert-butoxy, acetyl, cyclopropyl, cyclobutyl, cyclohexyl,        phenyl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl,        2,4-dihydro-3H-1,2,4-triazol-3-one-4-yl, 1H-imidazol-4-yl,        pyrazin-2-yl, pyrimidin-2-yl, 1,3-oxazolidin-2-one-5-yl,        N-benzamide, 4-methylpiperazin-1-yl, morpholin-4-yl, CF₃,        —SO₂—CH₃, —C(═O)-cyclopropyl, —NHCH₃, —N(CH₃)₂, —NHAc,        —NHCO₂t-Bu, —CH₂—NH₂, —C(═O)—NH₂, —C(═O)—N(ethyl)₂,        —NH—C(═O)—NH₂, —NH—C(═O)—CH₃, —C(═O)—(C₁-C₄alkyl), —C(═O)—OH,        —C(═O)—NH(C₁-C₄alkyl) —(CH₂)_(n)—OH, and —(CH₂)_(n)—CN, wherein        n is 1 or 2;    -   V is CH, CR′, or N, wherein R′ is methyl or F;    -   W is CR″ or N, wherein R″ is H, F, hydroxyl, amino, CH₃ or        —O—CH₃;    -   ring A is selected from the group consisting of:

-   -   R₃ is H, F, methyl, or —O—CH₃;    -   R₃′ is H or F;    -   R₄ is H, methyl, cyano, amino, halo, —COOH, or —O—CH₃;    -   R₅ is H, methyl, cyano, or —CF₃;    -   R₆ is H, cyano, amino, halo, or —CF₃; and    -   R₇ is halo, amino, —CONH₂, cyano, —O—CH₃, —CF₃, or —COO-ethyl.

Some embodiments are given by compounds of Formula (I), wherein ring Ais

In some of these embodiments, wherein ring A is

R₄ is H or cyano.

In some of these embodiments, wherein ring A is

R₅ is H or —CF₃.

In some of these embodiments, wherein ring A

R₆ is H, fluoro, chloro, or cyano.

Some embodiments are given by compounds of Formula (I), wherein ring Ais

Some embodiments are given by compounds of Formula (I), wherein V is CHand R₁ is H, halo, methyl, or CF₃.

Some embodiments are given by compounds of Formula (I), wherein R₃′ isH.

In some of these embodiments, wherein V is CH and R₁ is H, halo, methyl,or CF₃, the attachment point of R₁ to the phenyl ring is in the orthoposition with regard to V.

Some embodiments are given by compounds of Formula (I), wherein W is CF,R₃ is H, and R₃′ is H.

Some embodiments are given by compounds of Formula (I), wherein L is abond, —CH₂—, —SO₂—, —SO₂—NH—, —SO₂—NR—CH₂—, —CH₂—SO₂—NR—, —S—, —CH₂—S—,—O—, or —O—CH₂—.

In another embodiment, the present invention includes a compound ofFormula (I) wherein

L is a bond, —O—, —SO₂—NH—, —NH—SO₂—, —SO₂—, —S—, —C(═O)—, fluoro or—C(═O)—NH—;

R₁ is H, bromo or CF₃;

R₂ is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl,cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl,thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl,provided R₂ is not H if L is a bond, and wherein R₂ is optionallysubstituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH₂—NH₂;

V is CH or N;

W is CR″ or N, wherein R″ is H or F;

ring A is

R₃ is H;

R₃′ is H;

R₄ is H or cyano; and

R₅ is H or cyano.

In yet another embodiment, the present invention includes a compound ofFormula (I) wherein

L is a bond, —O—, —SO₂—NH—, —NH—SO₂—, —SO₂—, —S—, or —C(═O)—;

R₁ is H or CF₃;

R₂ is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl,cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl,thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl,provided R₂ is not H if L is a bond, and wherein R₂ is optionallysubstituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH₂—NH₂;

V is CH or N;

W is CR″ or N, wherein R″ is H or F;

ring A is

R₃ is H, and R₃′ is H.

The embodiments of the present invention also include the opticalisomers, hydrates, metabolites, enantiomers, diastereomers, cis-transisomers, racemates, prodrugs or pharmaceutically acceptable saltsthereof.

It is an embodiment of the present invention to provide a compoundselected from the compounds listed in Table 1.

TABLE 15-(3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,6-Amino-3-[3-fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazine-2-carbonitrile,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide (racemic),4′-(5-Aminopyrazin-2-yl)-N-(cyclobutylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(endo)-4′-(5-Aminopyrazin-2-yl)-N-bicyclo[2.2.1]hept-2-yl-3′-fluorobiphenyl-2-sulfonamide (racemic),4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methylcyclobutyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(1,1-dimethylpropyl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopentyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-phenylethyl)biphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-phenylethyl]biphenyl-2-sulfonamide, (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-1-methyl-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-pyridin-3-ylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfamide,N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)propane-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]propane-1-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-2-methylpropane-1-sulfonamide, N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]hexane-1-sulfonamide,N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclobutanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide,5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(4,4-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoroazetidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[2′-(Azepan-1-ylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(trifluoromethyl)piperidin-4-ol,5-(3-Fluoro-2′-{[4-(methylsulfonyl)piperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,5-{2′-[(4-Acetylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(2′-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,2-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanol,5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(3,5-Dimethylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-3-carbonitrile,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carbonitrile,5-{2′-[(4-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-ol,(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)methanol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)ethanol,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol,5-(3-Fluoro-2′-{[4-(methylamino)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,5-(2′-{[4-(Dimethylamino)piperidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,N-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide,(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)methanol, tert-Butyl(1-{[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)carbamate,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxypropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2R)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,(R)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(S)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-(2′-{[2-(Aminomethyl)pyrrolidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,(S)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(methylsulfonyl)biphenyl-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1-hydroxycyclohexyl)methyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-1,1-dimethylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(trans)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3,4-diol,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-sulfonamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-3-yl)methanol,(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-yl)methanol,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)biphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-phenylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol,(trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxycyclohexyl)biphenyl-2-sulfonamide, (trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide,(cis)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-piperidin-4-ylbiphenyl-2-sulfonamide,5-(2′-{[3-(Aminomethyl)azetidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-(azetidin-3-ylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-5-(3-Fluoro-2′-{[3-(methylamino)pyrrolidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide,5-[3-Fluoro-2′-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one,5-(2′-((1S,4S)2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-(2′-((1R,4R)2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-hydroxypentyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(6-hydroxyhexyl)biphenyl-2-sulfonamide,N-(4-Aminocyclohexyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2,3-dihydro-1H-indol-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,(S)-5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-bis(2-hydroxyethyl)biphenyl-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidine-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide,(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol,(1R,5S)-3-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-amine,(S)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(R)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperazin-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide, tert-Butyl[2-({[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]carbamate,N-(2-Aminoethyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxybutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(pyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide, N-[2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]acetamide,(S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)propanoic acid,4′-(5-Aminopyrazin-2-yl)-N-[2-(carbamoylamino)ethyl]-3′-fluorobiphenyl-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[6-(trifluoromethyl)pyridin-3-yl]biphenyl-2-sulfonamide,5-(3-Fluoro-2′-{[4-(1H-imidazol-4-yl)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,N-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2,6-dimethoxypyrimidin-4-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-methylpyrazin-2-yl)biphenyl-2-sulfonamide,(S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)-4-methylpentanamide,4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-methyloxetan-3-yl)biphenyl-2-sulfonamide,3-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)propanenitrile,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-methoxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,5-{3-Fluoro-2′-[(4-pyrazin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine, 5-(2′-Amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3-phenylpyrrolidin-3-ol,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide,N′-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide,(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol,(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol,(3′S,4′S)-1′-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-1,3′-bipyrrolidin-4′-ol,(3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-morpholin-4-ylpyrrolidin-3-ol,(3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol,5-{3-Fluoro-2′-[(trifluoromethyl)-sulfanyl]biphenyl-4-yl}pyrazin-2-amine,5-[2′-(tert-Butylsulfanyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Ethylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(propylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(2-methylpropyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclopentylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclobutylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(1-methylethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(trifluoromethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}acetamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}-N,N-diethylacetamide,5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfanyl]biphenyl-4-yl}pyrazin-2-amine, (racemic)5-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}methyl)-1,3-oxazolidin-2-one,N-(2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}ethyl)benzamide,5-(3-Fluoro-2′-{[4-(methylsulfonyl)benzyl]sulfanyl}biphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride,5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amineformate salt,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride,5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride, 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonamide formic acid salt,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(2-hydroxyethyl)methanesulfonamide formic acid salt,1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)azetidin-3-olformic acid salt,4-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperazin-2-one formic acid salt,(S)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)methanesulfonamide,(R)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)methanesulfonamide hydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(trans-4-hydroxycyclohexyl)methanesulfonamide,(S)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamide hydrochloride,(R)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamide,5-(2′-{[(4-Aminopiperidin-1-yl)sulfonyl]methyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine hydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamidehydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamideformate salt,1-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]urea hydrochloride,N-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]acetamide formate salt,5-{2′-[(Ethylsulfanyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amineformate salt,5-{3-Fluoro-2′-[(methylsulfanyl)methyl]biphenyl-4-yl}pyrazin-2-aminehydrochloride,5-(3-Fluoro-2′-{[(1-methylethyl)sulfanyl]methyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride,2-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-amine hydrochloride,6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-amine hydrochloride,5-(3-fluoro-2′-((pyridazin-3-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride,6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyridazin-3-amine hydrochloride,5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-aminehydrochloride,5-(3-fluoro-2′-((pyrimidin-4-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrazin-2-amine hydrochloride,5-(3-Fluoro-2′-{[3-(methylsulfonyl)propyl]sulfonyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride,5-(3-Fluoro-2′-{[(2R)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol,5-(3-Fluoro-2′-{[(2S)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3S)-piperidin-3-yl]biphenyl-2-sulfonamide,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3R)-piperidin-3-yl]biphenyl-2-sulfonamide,[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-yl]methanol,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(cis)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(trans)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]biphenyl-2-sulfonamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-oltrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3R)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopiperidin-3-yl]biphenyl-2-Sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-[(2S)-2,3-dihydroxypropyl]-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanol trifluoroacetic acid salt,[(2S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanol trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide trifluoroacetic acid salt,5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine trifluoroacetic acid salt,2-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanol trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-Sulfonamide trifluoroacetic acid,4′-(2-Aminopyrimidin-5-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-3′-fluoro-3-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,5-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetic acid salt,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-onetrifluoroacetic acid salt, tert-ButylN-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate,N-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alanine,N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide,N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide,N′-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide,5-(2′-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrimidin-2-amine,6-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide,1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)azetidine-3-carbonitrile,1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol,5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine hydrochloride,2-(((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)methyl)quinazolin-4(3H)-one,1-(3-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one,5-(2′-{[3-(Cyclohexylsulfonyl)propyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,5-{3-Fluoro-2′-[(1-methyl-1H-benzimidazol-2-yl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine,5-(2′-{[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-[3-fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,4-{[4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide, 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(5-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(4-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(5-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride,5-{2′-[(6-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amineformate salt,5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(5-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrimidin-2-amine formate salt,5-{2′-[(5-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrimidin-2-amine,5-(3-Fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-N,N-diethyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,5-(3-fluoro-2′-(pyrrolidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,5-(3-fluoro-2′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-aminopyridin-3-yl)-N-cyclohexyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-isobutyl-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(tert-pentyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-methylcyclobutyl)-[1,1′-biphenyl]-2-sulfonamide,4-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine1,1-dioxide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoropropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,5-(2′-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine, tert-butyl3-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide,2-(1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)ethanol,1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-ol,(1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)methanol,3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,3′-Fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,3′-Fluoro-N-(2-hydroxyethyl)-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]methanesulfonamide,3′-Fluoro-N,N-dimethyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,2-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,N,N-Diethyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,2-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,2-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide,2-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,3′-Fluoro-N-methyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,1-{[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-amine,2-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-5H-pyrrolo[2,3-b]pyrazine,2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,2-[2′-(Ethylsulfanyl)-3-fluorobiphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,7-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,7-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,1-{[4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-amine,4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,7-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,N-tert-Butyl-4′-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide,2-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]-5-(trifluoromethyl)pyridin-3-yl}phenyl)-5H-pyrrolo[2,3-b]pyrazine,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]pyridin-3-yl}phenyl)pyrazin-2-amine,2-{2-Fluoro-4-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine,2-{2-Fluoro-4-[2-(2-methylpropoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine,2-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine,2-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}-5H-pyrrolo[2,3-b]pyrazine,5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{4-[2-(Cyclopentyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,5-{4-[2-(Cyclohexyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,5-[2-Fluoro-4-(2-methoxypyridin-3-yl)phenyl]pyrazin-2-amine,5-{4-[2-(Cyclobutyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,tert-Butyl 3-[({3-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)methyl]pyrrolidine-1-carboxylate,5-{2-Fluoro-4-[2-(pyrrolidin-3-ylmethoxy)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-[4-(2-Aminopyridin-3-yl)-2-fluorophenyl]pyrimidin-2-amine,4′-(5-amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,3-Amino-6-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,3-Amino-6-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazine-2-carbonitrile,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,3-Amino-6-[3-fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazine-2-carbonitrile,4′-(6-Aminopyridazin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)biphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(1,8-naphthyridin-3-yl)biphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-quinoxalin-6-ylbiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(1H-indol-5-yl)biphenyl-2-sulfonamide,4′-(1H-Benzimidazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(1H-Benzimidazol-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(1,3-Benzothiazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[3,2-b]pyridin-6-yl)biphenyl-2-sulfonamide,3′-Fluoro-N-methyl-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-4′-(5,6-diaminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide,4′-(6-Amino-5-fluoropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-4′-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(3H-imidazo[4,5-b]pyridin-6-yl)biphenyl-2-sulfonamide,4′-(5-Amino-6-methoxypyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(6-Amino-4-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(6-amino-2-cyanopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-amino-1,3,4-thiadiazol-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4-((4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine 1,1-dioxide,4′-(5-Amino-6-chloropyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-bromopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,6-amino-3-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)picolinonitrile,N-tert-Butyl-3′-fluoro-4′-[1,2,4]triazolo[4,3-a]pyridin-7-ylbiphenyl-2-sulfonamide,4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide,N-tert-Butyl-4′-(5,6-diaminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(6-Amino-5-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(6-Amino-5-chloropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-[6-Amino-5-(trifluoromethyl)pyridin-3-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt,4′-[2-Amino-4-(trifluoromethyl)pyrimidin-5-yl]-N-tert-butyl-3′-fluorobiphenyl-2-Sulfonamide trifluoroacetic acid salt,4′-(2-Amino-4-methylpyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,N-tert-Butyl-3′-fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]biphenyl-2-sulfonamide,4′-(7-Amino-1H-indol-5-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide,3′-Fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methylbiphenyl-2-sulfonamide,4′-(7-Amino-1H-indol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]acetamide,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]urea,5-[2,3-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methylbiphenyl-2-yl]methanesulfonamide,4′-(5-Aminopyrazin-2-yl)-2′,3′-difluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-2′,3′-difluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[2′,3-Difluoro-4′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine,5-(2′,3-Difluorobiphenyl-4-yl)pyrazin-2-amine,5-(2′-Chloro-3-fluorobiphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-methylbiphenyl-4-yl)pyrazin-2-amine,5-[2′,3-Difluoro-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-(3-Fluoro-2′-methoxybiphenyl-4-yl)pyrazin-2-amine,5-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-ol,5-[3-Fluoro-2′-(phenylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-(2′,3,6′-Trifluorobiphenyl-4-yl)pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]benzenesulfonamide,5-(2′-Ethyl-3-fluorobiphenyl-4-yl)pyrazin-2-amine,{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid,5-[3-Fluoro-2′-(1-methylethyl)biphenyl-4-yl]pyrazin-2-amine,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanone,5-[3-Fluoro-2′-(2,2,2-trifluoroethoxy)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxylic acid,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxamide,5-[3-Fluoro-2′-(1-methylethoxy)biphenyl-4-yl]pyrazin-2-amine,5-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,2-[3,4′-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonmide,N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]ethanesulfonamide,N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylmethanesulfonamide,N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylethanesulfonamide,N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-2-methylpropane-1-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,2-dimethylpropane-1-sulfonamide,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrimidin-2-amine,2-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-carboxamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,5-[3-Fluoro-2′-(piperazin-1-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(4-Acetylpiperazin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-carboxamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-4-ol,5-{2′-[(4-Aminopiperidin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,4-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-2-amine,2-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-4-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-2-carbonitrile,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-3-carbonitrile,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-benzimidazole,6-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-3H-imidazo[4,5-b]pyridine,5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-4-amine,5-[3-Fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]methoxy}biphenyl-4-yl]pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol,5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′,4′-bis(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbonitrile,5-{5-[2-(Pyrimidin-2-yloxy)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine, 4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-5-(trifluoromethyl)phenoxy}pyrimidin-2-amine,5-{5-[2-(Pyrimidin-2-yloxy)phenyl]pyridin-2-yl}pyrimidin-2-amine,4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenoxy}pyrimidin-2-amine,5-(5-{2-[(4-Aminopyrimidin-2-yl)oxy]phenyl}pyridin-2-yl)pyrimidin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methoxybiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N,N-dimethylbiphenyl-2-sulfonamide,5-[2′-(Morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-2′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide,4′-(2-Amino-1,3-oxazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Amino-1,3-thiazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Amino-1,3-thiazol-4-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,4-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-1,3-thiazol-2-amine,N-tert-Butyl-3′-fluoro-4′-(8-fluoroimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide,4′-(5-Aminoimidazo[1,2-a]pyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide,2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide,N-tert-Butyl-4′-(5-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-4′-(6-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]biphenyl-2-sulfonamide, Ethyl2-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-5-carboxylate, andN-tert-Butyl-3′-fluoro-4′-(5-methoxyimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide. 5-[2′-(Methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine.5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine.4′-(5-Aminopyrazin-2-yl)-N,N,3′-trimethylbiphenyl-2-sulfonamide.4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl-2-sulfonamide.N-[4′-(5-Aminopyrazin-2-yl)biphenyl-2-yl]methanesulfonamide.4′-(5-Aminopyrazin-2-yl)biphenyl-2-sulfonamide.N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-sulfonamide.N-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2-sulfonamide.4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide.3-Amino-6-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylicacid.2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide.2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N-diethylacetamide.5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine.5,5′-(3,3″-Difluoro-1,1′:2′,1″-terphenyl-4,4″-diyl)dipyrazin-2-amine.4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid.4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde.5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine.5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine.2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol.5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine.5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine.5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile.6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile.5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-2-methylpyrimidin-4-amine.5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile.6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile.2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol.2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol.5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrazin-2-amine.5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrimidin-2-amine.5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine.5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine.5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine.5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine.5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrazin-2-amine.5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine.{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile.{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile.{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid.5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine.5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine.5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine.5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine.2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol.2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol.5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine.5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amineformic acid salt.5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine.5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine.(2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.(2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.(2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.(2l)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.N-(4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanesulfonamide5-(3-Fluoro-2′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetate5-(2′-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine4′-(6-Aminopyrazin-2-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-Sulfonamide4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide(racemic)-1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-ol4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamideN-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)acetamide2-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)ethanol.1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)methanol.2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide.2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide.2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide.5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine.5-{5-[2-(Morpholin-4-ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine.5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin-2-amine.5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt.5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt.5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt.5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethylbenzenesulfonamidetrifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamidetrifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide trifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide trifluoroacetic acid salt.4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulfonyl)piperazin-2-one.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide.5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide trifluoroacetic acid salt.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide.2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide.3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile trifluoroacetic acid salt.5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin-2-amine.5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H-pyrrolo[2,3-b]pyridine.5-(3-fluoro-2-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine.5-(2′,3,4′-Trifluorobiphenyl-4-yl)pyrazin-2-amine racemic5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carbonitrile1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)imidazolidin-2-one4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide6-Amino-3-{2′-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)-[1,1′-biphenyl]-2-Sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide6-Amino-3-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2-carbonitrileN-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3-dimethylbutan-2-one5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-(3-Fluoro-2′-(pyrimidin-4-ylthio)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2-carbonitrile6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrileN-(tert-Butyl)-3′-fluoro-4′-(5-(methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-aminehydrogen chloride salt5-{3-Fluoro-2′-[(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine5-(3-Fluoro-2′-{[(1-methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin-4-amineracemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-carboxamide5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(diastereomeric mixture).1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(diastereomeric mixture).4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol(cis/trans)4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol(cis/trans)4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide racemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine(diastereoisomeric mixture).5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine(diastereoisomeric mixture)5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2-amine2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-(3-hydroxyazetidin-1-yl)methanone[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[4-(methylamino)-1-piperidyl]methanone[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tetrahydropyran-4-yl-benzamide[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone racemic[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanoneN-{3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamideN-{3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamideN-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2-dimethylpropanamide racemic5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrazin-2-aminehydrochloride5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrimidin-2-amineformic acid salt.5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride.5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride5-(4-(2-(Cyclohexlsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride5-(4-(2-(Cyclohexylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidine-2-aminehydrochloride5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformic acid salt.5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformic acid salt. racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformate racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformate1-((3-(4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanone1-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanone hydrogen chloride salt5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-aminehydrogen chloride salt.5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-aminehydrogen chloride salt.4-((3-(4-(2-aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide4-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide5-(2-Fluoro-4-(2-((2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-amineformic acid salt.5-(2-Fluoro-4-(2-((2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-amine5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrimidin-2-amine formic acid salt.5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrazin-2-amine formic acid salt.5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine5-(2-Fluoro-4-(2-(isopropylsulfonyl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amineformic acid salt.5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amineformic acid salt.5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amineformic acid salt.5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine formic acid salt.5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride 5-(2,3-Difluorobiphenyl-4-yl)pyrazin-2-amine.5-(3-Fluoro-2-methoxybiphenyl-4-yl)pyrazin-2-amine.5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine.4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2′-methoxybiphenyl-2-sulfonamide.N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide.5-(3-Fluoro-2′-(pyrazin-2-yl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine5-(3-Fluoro-2′-pyrazin-2-ylbiphenyl-4-yl)pyrimidin-2-amine.5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrazin-2-amine.5-[2′-(5-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine.5-[2′-(6-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine.5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidin-2-amine.5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrimidin-2-amine.5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine.5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine.5-[3-Fluoro-2′-(1-methyl-1H-pyrazol-4-yl)biphenyl-4-yl]pyrazin-2-amine.5-(3-Fluoro-2′-pyrimidin-5-ylbiphenyl-4-yl)pyrazin-2-amine.5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidine-2-carbonitrile.5-[3-Fluoro-2′-(2-morpholin-4-ylpyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine.1-{4-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1H-pyrazol-1-yl}-2-methylpropan-2-ol.5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine.5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine.5-{2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]phenyl}pyrimidin-2-amine.5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine.5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine5-[2′-(1,1-Dioxido-1,2-thiazinan-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine5-[2-Fluoro-4-(2-pyrrolidin-1-ylpyridin-3-yl)phenyl]pyrazin-2-amine1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidin-2-one5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H-pyrrolo[2,3-b]pyridine5-(2′,3,4′-Trifluorobiphenyl-4-yl)pyrazin-2-amine5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine5-[2′-(Methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl-2-sulfonamideN-[4′-(5-Aminopyrazin-2-yl)biphenyl-2-yl]methanesulfonamide4′-(5-Aminopyrazin-2-yl)biphenyl-2-sulfonamide4′-(6-Aminopyridazin-3-yl)-3′-fluorobiphenyl-2-sulfonamideN-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2-sulfonamide3-Amino-6-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylicacid4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-(trifluoromethyl)biphenyl-2-Sulfonamide5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N-diethylacetamide5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine 5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin-2-amine5-{5-[2-(Morpholin-4-ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amineN-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-(2-Fluoro-4-{2-[(2-morpholin-4-ylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2-amine5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrimidin-2-amine2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol. {[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid.4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamid4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-carboxamide 5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrazin-2-amine5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazineN-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide4′-(5-Aminopyrazin-2-yl)-N,N,3′-trimethylbiphenyl-2-sulfonamide4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamideN-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-Sulfonamide4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrazin-2-amineN-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carbonitrile(2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine4′-(6-Aminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide5-{3-Fluoro-2′-[(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3-dimethylbutan-2-one6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineN-[4′-(6-Aminopyridin-3-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulfonyl)piperazin-2-one5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide5-{2-Fluoro-4-[2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethylbenzenesulfonamide(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol.(2S)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol 2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile(2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-methoxybiphenyl-2-sulfonamide5-(2-Fluoro-4-{2-[(3-methoxypropyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine 1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile5-{4-[2-(tert-Butylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine5-(2-Fluoro-4-{2-[(2-morpholin-4-ylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine5-(4-{2-[(1-Acetylpiperidin-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine 5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin-2-amine5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3-carboxamide5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3-carboxamide5-(2-Fluoro-4-{2-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine5-{2-Fluoro-4-[2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine6-Amino-3-{2′-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrileN-(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyridin-2-amine5-(3-Fluoro-2′-{[(1-methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile(2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamide5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine5-(2-Fluoro-4-{2-[(1-methylpropyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile5-{4-[2-(Cyclobutylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine5-(2-Fluoro-4-{2-[(3-methoxypropyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrile4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2′-methoxybiphenyl-2-sulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol5-(4-{2-[(1-Acetylpiperidin-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine2-(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)methanol6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine5-(2-Fluoro-4-{2-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine5-{4-[2-(tert-Butylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile 6-Amino-3-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2-carbonitrile4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxamide5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide5-{4-[2-(Cyclohexylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine5-{3-Fluoro-2′-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylsulfonyl]biphenyl-4-yl}pyrazin-2-amine1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carboxamide4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3-hydroxyazetidin-3-yl)methyl]biphenyl-2-sulfonamide5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin-4-amine4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbiphenyl-2-sulfonamide5-{4-[2-(Cyclopentylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine2-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbiphenyl-2-sulfonamide5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amineN,N-Diethyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-(2-Fluoro-4-{2-[(1-methylpropyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2-carbonitrile5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-{4-[2-(Cyclobutylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrazin-2-amine1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(pentafluoroethyl)piperidin-4-ol5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine 2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide tert-Butyl(1-{[3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-yl)carbamate5-{4-[2-(Cyclopentylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3,3′-difluorobiphenyl-2-sulfonamide5-{4-[2-(Cyclohexylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-sulfonamide5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-(2-fluoro-4-(2-(piperidin-4-yloxy)pyridin-3-yl)phenyl)pyrazin-2-amine5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine N-{3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamideN-{3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineN-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2-dimethylpropanamide

Particularly, an embodiment of the present invention comprises acompound selected from the compounds listed in Table 2.

TABLE 2N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,5-(3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetic acid salt,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-{2′-[(4-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-2′,3′-difluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(5-Amino-6-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(5-Amino-3-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide, (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1- methylethyl]biphenyl-2-sulfonamide,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2,3-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{4-[2-(Cyclopentyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,(R)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide, 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-methylcyclobutyl)-[1,1′-biphenyl]-2- sulfonamide,4-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine1,1-dioxide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,5-{3-Fluoro-2′-[(trifluoromethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-ol,(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)methanol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)ethanol,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol,5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,N-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,(S)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(S)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxypropyl)biphenyl-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-3-yl)methanol,N-tert-Butyl-3′-fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol,5-(2′-{[2-(Aminomethyl)pyrrolidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide trifluoroacetic acid salt,N-(2-Aminoethyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(pyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,(cis)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamide trifluoroacetic acid salt,(S)-5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine, 4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1- methylethyl]biphenyl-2-sulfonamide,(1R,5S)-3-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,2-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-5H-pyrrolo[2,3-b]pyrazine,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-[1,1′- biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)-4-methylpentanamide,2-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-methyloxetan-3-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrimidin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-2-sulfonamide, 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide, 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(5-amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,N′-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide,5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide, 5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrazin-2-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidin-2-amine,5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-{2′-[(5-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amineformate salt,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-aminehydrochloride,4′-(5-amino-1,3,4-thiadiazol-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride,4-((4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine 1,1-dioxide,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide, and4′-(5-Amino-6-chloropyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide.

The invention is also directed to a pharmaceutical composition whichinclude, without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carriers or excipients.

Another embodiment of the present invention is a pharmaceuticalcomposition of the present invention that comprises at least a compoundselected from the compounds listed in Table 1.

Particularly, an embodiment of the present invention is a pharmaceuticalcomposition of the present invention that comprises at least a compoundselected from the compounds listed in Table 2.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease and/or disorder mediated byFLAP activity, comprising administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I).

The present invention also features a method for preventing, treating,ameliorating, including without limitation inhibiting, the progressionof an FLAP-mediated disease and/or disorder in a subject in needthereof, comprising administering to said subject a therapeuticallyeffective amount of at least one compound of Formula (I). Such a diseaseand/or disorder includes, but is not limited to diabetes, respiratorydisorders, and associated symptoms or complications thereof. Morespecifically, this invention is directed to a method of treating, butnot limited to, exacerbations, non-allergic asthma, fibrotic lungdiseases, acute respiratory distress syndrome and chronic obstructivepulmonary disease, and their associated symptoms or complications, in asubject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are usefulfor the amelioration of symptoms associated with and/or the treatment ofthe following cardiac and cardiovascular diseases and/or disorders:myocardial infarction, atherosclerosis and stroke aortic aneurisms,atherosclerosis, or associated symptoms or complications thereof, in asubject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are usefulfor the amelioration of symptoms associated with and/or the treatment ofautoimmune or allergic diseases and/or disorders, wherein saidautoimmune or allergic diseases and/or disorders include, but are notlimited to, rheumatoid arthritis, inflammatory bowel disease, nephritis,spondyloarthritis, polymyositis, dermatomyositis, gouty effusions,systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease,multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder. In a further embodiment, thecompounds of the present invention are useful for the amelioration ofsymptoms associated with and/or the prophylaxis or treatment ofcarcinogenesis, wherein said carcinogenesis include, but is not limitedto, tumor cell proliferation, differentiation, and apoptosis,tumor-associated angiogenesis, as well as the migration and invasion ofcarcinoma cells.

It is a further embodiment of the invention to provide a process formaking a pharmaceutical composition comprising admixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

In a further embodiment of the invention, a method for treating orameliorating an FLAP-mediated disease and/or disorder in a subject inneed thereof comprises administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5 g/dose. In particular, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.5mg/dose to about 1000 mg/dose.

More particularly, the therapeutically effective amount of the compoundof Formula (I) is from about 1 mg/dose to about 100 mg/dose. In afurther embodiment of the invention, the number of doses per day of acompound of Formula (I) is from 1 to 3 doses. In a further embodiment ofthe invention, the therapeutically effective amount of the compound ofFormula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. Moreparticularly, the therapeutically effective amount of the compound ofFormula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout thisdisclosure.

It should also be noted that any atom with unsatisfied valences in thetext, chemes, examples, structural formulae and any tables herein isassumed to have the hydrogen atom or atoms to satisfy the valences.

As used herein, the following terms are intended to have the followingdefinitions. The definitions herein may specify that a chemical term hasan indicated formula. The particular formula provided is not intended tolimit the scope of the invention, but is provided as an illustration ofthe term. The scope of the per se definition of the term is intended toinclude the plurality of variations expected to be included by one ofordinary skill in the art.

The term “C₁₋₆alkyl” means a saturated branched or straight-chainhydrocarbon radical having from 1 up to 6 carbon atoms in a linear orbranched arrangement, selected from the group consisting of methyl,ethyl, propyl, butyl, pentyl, and hexyl. Examples include isopropyl,isobutyl, tert-butyl, sec-butyl, n-butyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 1,2-dimethylpropyl, butan-2-yl, 2-methylbutyl,2-methylbutan-2-yl, 1-methyl-3-methylbutyl, 3,3-dimethylbutan-2-yl, andthe like, and all that are exemplified in the below examples. An alkylradical may be attached to a core molecule by any atom where allowed byavailable valences. The term “C₁₋₄alkyl” means a saturated branched orstraight-chain hydrocarbon radical having from 1 up to 4 carbon atoms ina linear or branched arrangement,

The term “C₃₋₉cycloalkyl” means a saturated or partially unsaturated,monocyclic, polycyclic or benzofused hydrocarbon ring system radical.Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptan-2-yl, 2,3-dihydro-1H-inden-2-yl, and the like, andall that are exemplified in the below examples. A C₃₋₉cycloalkyl radicalmay be attached to a core molecule by any ring atom where allowed byavailable valences.

The term “aryl” means an unsaturated, aromatic monocyclic or polycyclichydrocarbon ring system radical. Examples include phenyl and the like,and all that are exemplified in the below examples. An aryl radical maybe attached to a core molecule by any ring atom where allowed byavailable valences.

The term “hetero”, when used as a prefix for a ring system, refers tothe replacement of at least one carbon atom member in the ring systemwith a heteroatom selected from N, O, S, S(O), or SO₂. A hetero ring mayhave 1, 2, 3 or 4 carbon atom members replaced by a nitrogen atom.Alternatively, a ring may have 1, 2 or 3 nitrogen atom members and 1oxygen or sulfur atom member. Alternatively, a ring may have 1 oxygen orsulfur atom member. Alternatively, up to two adjacent ring members maybe heteroatoms, wherein one heteroatom is nitrogen and the otherheteroatom is selected from N, S or O.

The term “heteroaryl” means an unsaturated monocyclic, polycyclicaromatic “hetero” ring system radical, selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,benzimidazolyl, and tetrazolyl. Examples include pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrazin-2-yl, pyrazin-4-yl,pyrimidin-2-yl, pyridazin-3-yl, 1H-benzimidazol-2-yl, 2H-tetrazol-5-yl,and the like, and all that are exemplified in the below examples. Aheteroaryl radical may be attached to a core molecule by any ring atomwhere allowed by available valences.

The term “heterocyclyl” means a saturated monocyclic or polycyclic“hetero” ring system radical, selected from the group consisting ofazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,pyrazoyl, thiomorpholinyl, azepanyl, hexahydropyrrolo[1,2-a]pyrazinyl,tetrahydropyrazolo[4,3-c]pyridinyl, diazabicyclo[2.2.1]-heptanyl,dihydro-indolyl, tetrahydropyranyl, azabicyclo[3.1.0]hexanyl, oxetanyl,isothiazolidinyl, thiazinanyl, thiopyranyl, thia-azaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, tetrahydro-thiopyranyl, dihydroquinazolinyl,oxadiazolyl, oxa-azabicylco[2.2.1]heptanyl, piperazin-2-one-yl,2-oxa-5-azabicyclo[2.2.1]heptanyl, pyrrolidin-2-one-yl,imidazolidin-2-one-yl, 1,2-thiazinane 1,1-dioxide-yl, isothiazolidine1,1-dioxide-yl, 1,2,3,6-tetrahydropyridinyl, and imidazolidinyl.Examples include azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, piperazin-1-yl, morpholin-2-yl, morpholin-4-yl,thiomorpholin-4-yl, azepan-1-yl, azepan-3-yl,hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl,1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-yl,2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,3-dihydro-1H-indol-2-yl,tetrahydro-2H-pyran-4-yl, 3-azabicyclo[3.1.0]hexan-3-yl, oxetan-3-yl,isothiazolidin-2-yl, 1,2-thiazinan-2-yl, 2H-thiopyran-4-yl,2-thia-6-azaspiro[3.3]heptan-6-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl,tetrahydro-2H-thiopyran-4-yl, 3,4-dihydroquinazolin-2-yl,1,2,3-oxadiazol-5-yl, 2-oxa-5-azabicylco[2.2.1]heptan-5-yl,imidazolidin-1-yl, thiomorpholine 1,1-dioxide-yl,4-amino-tetrahydro-2H-pyran-yl, tetrahydro-2H-thiopyran 1,1-dioxide-yl,and the like, and all that are exemplified in the below examples. Aheterocyclyl radical may be attached to a core molecule by any ring atomwhere allowed by available valences.

The term “carboxy” means a radical of the formula: —C(O)OH.

The term “halogen” or “halo” means a radical selected from the groupconsisting of chloro, bromo, fluoro or iodo.

The term “oxo” means a radical of the formula: ═O.

The term “substituted” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). In a preferred embodiment, up to three hydrogen atomsare each independently replaced.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

In general, IUPAC nomenclature rules are used herein.

The term “about,” whether used explicitly or not in reference to aquantitative expression given herein, means that every quantity givenherein qualified with the term or otherwise is meant to refer both tothe actual given value and the approximation to such given value thatwould reasonably be inferred based on the ordinary skill in the art,including approximations due to experimental and/or measurementconditions for such given value.

The term “form” means, in reference to compounds of the presentinvention, such may exist as, without limitation in the followingstates, a salt, stereoisomer, tautomer, crystalline, polymorph,amorphous, solvate, hydrate, ester, prodrug or metabolite form. Thepresent invention encompasses all such compound forms and mixturesthereof.

The term “isolated form” means, in reference to compounds of the presentinvention, such may exist in an essentially pure state such as, withoutlimitation, an enantiomer, a racemic mixture, a geometric isomer (suchas a cis or trans stereoisomer), a mixture of geometric isomers, and thelike. The present invention encompasses all such compound forms andmixtures thereof.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “subject” as used herein, refers to a patient, such as ananimal, a mammal or a human, who has been the object of treatment,observation or experiment and is at risk of (or susceptible to)developing an FLAP-mediated disorder.

The term “administering” further means that the individual ingredientsto be combined may be administered at the same time or at differenttimes during the treatment period, either as one preparation or asdifferent preparations. Accordingly, the invention should be sointerpreted that it encompasses any and every administration mode at thesame time or at different times. The range of the combination of thecompound of the invention and the other therapeutic agent useful for theabove-mentioned disorders encompasses, in principle, all combinations ofthe compound of the invention and any and every pharmaceutical agentuseful for the above-mentioned disorders.

The term “treating” refers, without limitation, to facilitating theeradication of, preventing, ameliorating or otherwise inhibiting theprogression of or promoting stasis of an FLAP-mediated disease and/ordisorder, or associated symptoms or complications thereof.

The term “prodrug” means a compound of Formula (I) or a form thereofthat is converted in vivo into a functional derivative form that maycontribute to therapeutic biological activity, wherein the convertedform may be: 1) a relatively active form; 2) a relatively inactive form;3) a relatively less active form; or, 4) any form which results,directly or indirectly, from such in vivo conversions. Prodrugs areuseful when said compound may be either too toxic to administersystemically, absorbed poorly by the digestive tract or broken down bythe body before it reaches its target. Conventional procedures for theselection and preparation of suitable prodrug derivatives are describedin, for example, “Design of Prodruqs”, ed. H. Bundgaard, Elsevier, 1985.

The term “metabolite” means a prodrug form of a compound of Formula (I)or a form thereof converted by in vivo metabolism or a metabolic processto a relatively less active functional derivative of said compound.

The term “medicament” or “medicine” refers to a product containing acompound of Formula (I) or a form thereof. The present inventionincludes use of such a medicament for treating an FLAP-mediateddisorder.

The term “combination form” refers to the use of a combination productcomprising a compound of Formula (I) or a form, pharmaceuticalcomposition, medicine or medicament thereof and at least one therapeuticagent for treating an FLAP-mediated disorder.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition.

For therapeutic purposes, the term “therapeutically effective amount” or“effective amount” as used herein, means that amount of each activecompound or pharmaceutical agent, alone or in combination, that elicitsthe biological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease and/or disorder being treated. For prophylactic purposes (i.e.,inhibiting the progression of a disorder), the term “therapeuticallyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that treats or inhibitsin a subject the progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician. Thus, thepresent invention provides combinations of two or more drugs wherein,for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. The effective amount of saidcompound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Advantageously, the effective amount of a combination product fortreating an FLAP-mediated disease and/or disorder, or associatedsymptoms or complications thereof, may be a reduced amount of either orboth, the compound or therapeutic agent, compared to the effectiveamount of the compound or therapeutic agent otherwise recommended fortreating the disease and/or disorder, or associated symptoms orcomplications thereof. Therefore, it is contemplated that the compoundis administered to the subject before, during or after the time theagent is administered.

The term “pharmaceutically acceptable salt” refers to non-toxicpharmaceutically acceptable salts (Ref. Int'l J. Pharm., 1986, 33:201-217; J. Pharm. Sci., 1997 (January), 66(1): 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which may, for example,be formed by mixing a solution of the compound according to theinvention with a solution of an acid such as acetic acid, adipic acid,benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid,hydrochloric acid, maleic acid, malonic acid, phosphoric acid,saccharinic acid, succinic acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable salts thereof may include alkali metal salts, e.g.sodium or potassium salts; alkaline earth metal salts, e.g. calcium ormagnesium salts; and salts formed with suitable organic ligands, e.g.quaternary ammonium salts.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999.The protecting groups may be removed at a convenient subsequent stageusing methods known in the art. The scope of the present inventionencompasses all such protected compound forms and mixtures thereof.

The invention includes compounds of various isomers and mixturesthereof. The term “isomer” refers to compounds that have the samecomposition and molecular weight but differ in physical and/or chemicalproperties. Such substances have the same number and kind of atoms butdiffer in structure. The structural difference may be in constitution(geometric isomers) or in an ability to rotate the plane of polarizedlight (optical isomers).

The term “stereoisomer” refers to isomers that have the same molecularformula and the same sequence of covalently bonded atoms but a differentspatial orientation.

The term “optical isomer” means isomers of identical constitution thatdiffer only in the spatial arrangement of their groups. Optical isomersrotate the plane of polarized light in different directions. The term“optical activity” means the degree to which an optical isomer rotatesthe plane of polarized light.

The term “racemate” or “racemic” means an equimolar mixture of twoenantiomeric species, wherein each of the isolated species rotates theplane of polarized light in the opposite direction such that the mixtureis devoid of optical activity.

The term “enantiomer” means an isomer having a nonsuperimposable mirrorimage. The term “diastereomer” means stereoisomers that are notenantiomers.

The term “chiral” means a molecule that, in a given configuration,cannot be superimposed on its mirror image. This is in contrast toachiral molecules that can be superimposed on their mirror images.

The two distinct mirror image versions of the chiral molecule are alsoknown as levo (left-handed), abbreviated L, or dextro (right-handed),abbreviated D, depending on which way they rotate polarized light. Thesymbols “R” and “S” represent the configuration of groups around astereogenic carbon atom(s).

The term “geometric isomer” means isomers that differ in the orientationof substituent atoms in relationship to a carbon-carbon double bond, toa cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms(other than hydrogen) on each side of a carbon-carbon double bond may bein an E or Z configuration according to the Cahn-Ingold-Prelog priorityrules. In the “E” configuration, the substituents having the highestpriorities are on opposite sides in relationship to the carbon-carbondouble bond. In the “Z” configuration, the substituents having thehighest priorities are oriented on the same side in relationship to thecarbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may bein a cis or trans configuration. In the “cis” configuration, thesubstituents are on the same side in relationship to the plane of thering; in the “trans” configuration, the substituents are on oppositesides in relationship to the plane of the ring. Compounds having amixture of “cis” and “trans” species are designated “cis/trans”.

The isomeric descriptors (“R,” “S,” “E,” and “Z”) indicate atomconfigurations and are intended to be used as defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and, as such, are intended tobe included in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents (e.g., organic esters such as ethanolate and the like)and, as such, are also intended to be encompassed within the scope ofthis invention.

B) Compounds

Representative compounds of the present invention are listed in Table 3below:

TABLE 3 COM- STRUCTURE POUND # NAME

1 5-(3-fluoro-2′-(methylsulfonyl)[1,1′-biphenyl]- 4-yl)pyrazin-2-amine

2 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]methanesulfonamide

3 6-Amino-3-[3-fluoro-2′- (methylsulfonyl)biphenyl-4-yl]pyrazine-2-carbonitrile

4 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′- fluorobiphenyl-2-sulfonamide

5 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′- biphenyl]-2-sulfonamide

6 4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′- fluorobiphenyl-2-sulfonamide

7 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide

8 (racemic)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2- sulfonamide racemic

9 4′-(5-Aminopyrazin-2-yl)-N-(cyclobutylmethyl)-3′-fluorobiphenyl-2-sulfonamide

10 (racemic)-(endo)-4′-(5-Aminopyrazin-2-yl)-N-bicyclo[2.2.1]hept-2-yl-3′-fluorobiphenyl-2- sulfonamide racemic

11 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methylcyclobutyl)biphenyl-2-sulfonamide

12 4′-(5-Aminopyrazin-2-yl)-N-(1,1- dimethylpropyl)-3′-fluorobiphenyl-2-sulfonamide

13 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2- sulfonamide

14 4′-(5-Aminopyrazin-2-yl)-N-cyclopentyl-3′-fluorobiphenyl-2-sulfonamide

15 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N- methylbiphenyl-2-sulfonamide

16 4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′- fluorobiphenyl-2-sulfonamide

17 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-phenylethyl)biphenyl-2-sulfonamide

18 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2- sulfonamide

19 (S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2- sulfonamide

20 (S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- sulfonamide

21 4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)-3′-fluorobiphenyl-2-sulfonamide

22 (S)-4′-(5-Aminopyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2- sulfonamide

23 (R)-4′-(5-Aminopyrazin-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2- sulfonamide

24 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-phenylethyl]biphenyl-2-sulfonamide

25 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2- sulfonamide

26 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N- phenylbiphenyl-2-sulfonamide

27 (S)-4′-(5-Aminopyrazin-2-yl)-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]-3′-fluorobiphenyl-2- sulfonamide

28 (S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-2-oxoazepan-3-yl]biphenyl-2-sulfonamide

29 (S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-1-methyl-2-oxoazepan-3-yl]biphenyl-2- sulfonamide

30 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)biphenyl- 2-sulfonamide

31 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-pyridin-3-ylbiphenyl-2-sulfonamide

32 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

33 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]sulfamide

34 N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)propane-2-sulfonamide

35 N-(4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]ethanesulfonamide

36 N-(4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]propane-1-sulfonamide

37 N-(4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-2-methylpropane-1-sulfonamide

38 N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropanesulfonamide

39 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]hexane-1-sulfonamide

40 N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclobutanesulfonamide

41 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide

42 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide

43 5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl- 4-yl]pyrazin-2-amine

44 5-[3-Fluoro-2′-(morpholin-4- ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

45 5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

46 5-[3-Fluoro-2′-(piperazin-1- ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

47 4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′- fluorobiphenyl-2-sulfonamide

48 5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

49 5-{2′-[(4,4-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

50 5-{2′-[(3,3-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

51 5-{2′-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

52 5-{2′-[(3,3-Difluoroazetidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

53 5-[2′-(Azepan-1-ylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

54 5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

55 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(trifluoromethyl)piperidin-4-ol

56 5-(3-Fluoro-2′-{[4-(methylsulfonyl)piperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

57 5-{2′-[(4-Acetylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

58 5-(2′-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2- amine

59 2-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1- yl)ethanol

60 5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

61 5-[3-Fluoro-2′-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

62 5-{2′-[(3,5-Dimethylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

63 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-3-carbonitrile

64 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carbonitrile

65 5-{2′-[(4-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

66 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one

67 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-ol

68 (1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4- yl)methanol

69 2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4- yl)ethanol

70 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol

71 2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pipendin-3- yl)ethanol

72 5-(3-Fluoro-2′-{[4-(methylamino)pipendin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

73 5-(2′-{[4-(Dimethylamino)piperidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2- amine

74 5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

75 N-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4- yl)acetamide

76 (1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3- yl)methanol

77 tert-Butyl (1-{[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3- yl)carbamate

78 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2- phenylethyl]biphenyl-2-sulfonamide

79 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]biphenyl-2- sulfonamide

80 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxypropyl)biphenyl-2-sulfonamide

81 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide

82 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide

83 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]biphenyl-2- sulfonamide

84 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]biphenyl-2- sulfonamide

85 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2R)-2-hydroxycycloethyl]biphenyl-2-sulfonamide

86 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)propyl]biphenyl-2- sulfonamide

87 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

88 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

89 4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

90 4′-(5-Aminopyrazin-2-yl)-N- (cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamide

91 (R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2- yl)methanol

92 (R)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

93 (S)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

94 5-(2′-{[2-(Aminomethyl)pyrrolidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2- amine

95 (S)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2- yl)methanol

96 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(methylsulfonyl)biphenyl-2-sulfonamide

97 (R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide

98 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide

99 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1-hydroxycyclohexyl)methyl]biphenyl-2- sulfonamide

100 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2- sulfonamide

101 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2- sulfonamide

102 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-1,1-dimethylpropyl)biphenyl-2- sulfonamide

103 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2- sulfonamide

104 (S)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2- sulfonamide

105 (R)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2- sulfonamide

106 (trans)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3,4-diol

107 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopyrrolidin-3-yl)-[1,1′-biphenyl]-2- sulfonamide

108 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)-[1,1′-biphenyl]-2- sulfonamide

109 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)-2-methylpropyl]biphenyl-2- sulfonamide

110 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-sulfonamide

111 (R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-3- yl)methanol

112 (S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3- yl)methanol

113 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)biphenyl-2-sulfonamide

114 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide

115 (S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide

116 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-phenylpropan-2-yl)-[1,1′-biphenyl]- 2-sulfonamide

117 (R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-phenylethyl)-[1,1′-biphenyl]-2- sulfonamide

118 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl- [1,1′-biphenyl]-2-sulfonamide

119 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol

120 (trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxycyclohexyl)biphenyl-2-sulfonamide

121 (trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2- sulfonamide

122 (cis)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2- sulfonamide

123 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-piperidin-4-ylbiphenyl-2-sulfonamide

124 5-(2′-{[3-(Aminomethyl)azetidin-1-yl]sulfonyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine

125 4′-(5-Aminopyrazin-2-yl)-N-(azetidin-3-ylmethyl)-3′-fluorobiphenyl-2-sulfonamide

126 (R)-5-(3-Fluoro-2′-{[3-(methylamino)pyrrolidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

127 (R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2- sulfonamide

128 5-[3-Fluoro-2′-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-ylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

129 4-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

130 5-(2′-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4- yl)pyrazin-2-amine

131 5-(2′-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4- yl)pyrazin-2-amine

132 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-hydroxypentyl)biphenyl-2-sulfonamide

133 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(6-hydroxyhexyl)biphenyl-2-sulfonamide

134 N-(4-Aminocyclohexyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

135 (S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2,3-dihydro-1H- indol-2-yl)methanol

136 4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2- sulfonamide

137 (S)-5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

138 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-bis(2-hydroxyethyl)biphenyl-2-sulfonamide

139 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidine-2-carboxamide

140 4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2- sulfonamide

141 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2- sulfonamide

142 (4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2- yl)methanol

143 (1R,5S)-3-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3- azabicyclo[3.1.0]hexan-6-amine

144 (S)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2- amine

145 (R)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2- amine

146 (R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperazin-2- yl)methanol

147 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1- methylethyl]biphenyl-2-sulfonamide

148 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

149 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′- biphenyl]-2-sulfonamide

150 (R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′- biphenyl]-2-sulfonamide

151 tert-Butyl [2-({[4′-(5-aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]carbamate

152 N-(2-Aminoethyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

153 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxybutan-2-yl)-[1,1′-[1,1′-2- sulfonamide

154 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(pyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide

155 N-[2-({[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]acetamide

156 (S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)propanoic acid

157 4′-(5-Aminopyrazin-2-yl)-N-[2-(carbamoylamino)ethyl]-3′-fluorobiphenyl-2- sulfonamide

158 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-[1,1′-biphenyl]-2-sulfonamide

159 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′- biphenyl]-2-sulfonamide

160 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′- biphenyl]-2-sulfonamide

161 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′- biphenyl]-2-sulfonamide

162 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxycyclohexyly[1,1′-biphenyl]-2- sulfonamide

163 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[6-(trifluoromethyl)pyridin-3-yl]biphenyl-2- sulfonamide

164 5-(3-Fluoro-2′-{[4-(1H-imidazol-4-yl)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

165 N-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2- sulfonamide

166 4′-(5-Aminopyrazin-2-yl)-N-(2,6-dimethoxypyrimidin-4-yl)-3′-fluorobiphenyl-2- sulfonamide

167 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-methylpyrazin-2-yl)biphenyl-2-sulfonamide

168 (S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)-4- methylpentanamide

169 4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide

170 (R)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2- sulfonamide

171 (S)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2- sulfonamide

172 4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

173 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-methyloxetan-3-yl)biphenyl-2-sulfonamide

174 3-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1- yl)propanenitrile

175 (S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-methoxypropan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

176 5-{3-Fluoro-2′-[(4-pyrazin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

177 5-{3-Fluoro-2′-[(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

178 5-(2′-Amino-3-fluorobiphenyl-4-yl)pyrazin-2- amine

179 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2- sulfonamide

180 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3-phenylpyrrolidin-3-ol

181 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide

182 N′-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide

183 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide

184 (3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol

185 (3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol

186 (3′S,4′S)-1′-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-1,3′-bipyrrolidin- 4′-ol

187 (3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-morpholin-4- ylpyrrolidin-3-ol

188 (3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(4- methylpiperazin-1-yl)pyrrolidin-3-ol

189 5-{3-Fluoro-2′-[(trifluoromethyl)-sulfanyl[biphenyl-4-yl}pyrazin-2-amine

190 5-[2′-(tert-Butylsulfanyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

191 5-[2′-(Ethylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

192 5-[3-Fluoro-2′-(propylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

193 5-{3-Fluoro-2′-[(2- methylpropyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

194 5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

195 5-[2′-(Cyclopentylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

196 5-[2′-(Cyclobutylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

197 5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4- yl]pyrazin-2-amine

198 5-[3-Fluoro-2′-(hexylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

199 5-{3-Fluoro-2′-[(1- methylethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

200 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}acetamide

201 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}-N,N-diethylacetamide

202 5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfanyl]biphenyl-4-yl}pyrazin-2- amine

203 (racemic) 5-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}methyl)-1,3- oxazolidin-2-one

204 N-(2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}ethyl)benzamide

205 5-(3-Fluoro-2′-{[4- (methylsulfonyl)benzyl]sulfanyl}biphenyl-4-yl)pyrazin-2-amine

206 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

207 5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

208 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide

209 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2- yl]sulfonyl}piperazin-2-one

210 4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2- sulfonamide

211 4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

212 5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4- yl}pyrazin-2-amine

213 5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-amine hydrochloride

214 5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amine formate salt

215 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-amine hydrochloride

216 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-amine hydrochloride

217 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-amine hydrochloride

218 5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl- 4-yl]pyrazin-2-aminehydrochloride

219 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-amine hydrochloride

220 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonamide formic acid salt

221 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(2-hydroxyethyl)methanesulfonamide formic acid salt

222 1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)azetidin-3- ol formic acid salt

223 4-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperazin- 2-one formic acid salt

224 (S)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2- yl)methanesulfonamide

225 (R)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2- yl)methanesulfonamidehydrochloride

226 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]-N-(trans-4-hydroxycyclohexyl)methanesulfonamide

227 (S)-1-[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamide hydrochloride

228 (R)-1-[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamide

229 5-(2′-{[(4-Aminopiperidin-1-yl)sulfonyl]methyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine hydrochloride

230 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide hydrochloride

231 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamide formate salt

232 1-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin- 4-yl]urea hydrochloride

233 N-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin- 4-yl]acetamide formatesalt

234 5-{2′-[(Ethylsulfanyl)methyl]-3-fluorobiphenyl- 4-yl}pyrazin-2-amineformate salt

235 5-{3-Fluoro-2′- [(methylsulfanyl)methyl]biphenyl-4-yl}pyrazin-2-amine hydrochloride

236 5-(3-Fluoro-2′-{[(1- methylethyl)sulfanyl]methyl}biphenyl-4-yl)pyrazin-2-amine hydrochloride

237 2-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-amine hydrochloride

238 6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-amine hydrochloride

239 5-(3-fluoro-2′-((pyridazin-3-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine hydrochloride

240 6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyridazin-3-amine hydrochloride

241 5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2- amine

242 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amine hydrochloride

243 5-(3-fluoro-2′-((pyrimidin-4-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine hydrochloride

244 5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl- 4-yl]pyrazin-2-amine

245 5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl- 4-yl]pyrazin-2-aminehydrochloride

246 5-(3-Fluoro-2′-{[3- (methylsulfonyl)propyl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine hydrochloride

247 5-(3-Fluoro-2′-{[(2R)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine

248 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)propyl]biphenyl-2- sulfonamide

249 4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

250 4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide

251 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2- sulfonamide

252 (4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2- yl)methanol

253 5-(3-Fluoro-2′-{[(2S)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine

254 5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4- yl]pyrimidin-2-amine

255 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1- methylethyl]biphenyl-2-sulfonamide

256 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3S)-piperidin-3-yl]biphenyl-2-sulfonamide

257 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3R)-piperidin-3-yl]biphenyl-2-sulfonamide

258 [(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2- yl]methanol

259 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(cis)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

260 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(trans)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

261 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2- sulfonamide

262 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-2-sulfonamide

263 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]biphenyl-2-sulfonamide

264 5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

265 1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol trifluoroacetic acid salt

266 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3R)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamide trifluoroacetic acid salt

267 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamide trifluoroacetic acid salt

268 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

269 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl- 2-sulfonamidetrifluoroacetic acid salt

270 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl- 2-sulfonamidetrifluoroacetic acid salt

271 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

272 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2- sulfonamide trifluoroacetic acid salt

273 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

274 4′-(2-Aminopyrimidin-5-yl)-N-[(2S)-2,3-dihydroxypropyl]-3′-fluorobiphenyl-2- sulfonamide trifluoroacetic acidsalt

275 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide trifluoroacetic acid salt

276 [(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2- yl]methanol trifluoroaceticacid salt

277 [(2S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2- yl]methanol trifluoroaceticacid salt

278 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide

279 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide trifluoroacetic acid salt

280 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2- sulfonamide trifluoroacetic acidsalt

281 5-{2′-[(4-Cyclopropylpiperazin-1-yl]sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine trifluoroacetic acid salt

282 2-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1- yl)ethanol trifluoroaceticacid salt

283 4′-(2-Aminopyrimidin-5-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2- sulfonamide trifluoroaceticacid

284 4′-(2-Aminopyrimidin-5-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

285 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N- phenylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

286 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt

287 4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-3′-fluoro-3-methylbiphenyl-2-sulfonamide trifluoroacetic acid salt

288 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N- methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

289 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide trifluoroacetic acid salt

290 5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine trifluoroacetic acid salt

291 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

292 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

293 5[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4- yl]pyrimidin-2-aminetrifluoroacetic acid salt

294 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide trifluoroacetic acid salt

295 4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′- fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

296 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2- sulfonamide trifluoroacetic acidsalt

297 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- sulfonamide trifluoroaceticacid salt

298 5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine trifluoroacetic acid salt

299 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide trifluoroacetic acid salt

300 4′-(2-Aminopyrimidin-5-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

301 5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine trifluoroacetic acid salt

302 4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2- sulfonamidetrifluoroacetic acid salt

303 5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine trifluoroacetic acid salt

304 5-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4- yl]pyrimidin-2-aminetrifluoroacetic acid salt

305 4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide trifluoroacetic acid salt

306 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one trifluoroacetic acid salt

307 tert-Butyl N-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate

308 N-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alanine

309 N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide

310 N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide

311 N′-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide

312 5-(2′-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4- yl)pyrimidin-2-amine

313 6-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-2-thia-6- azaspiro[3.3]heptane2,2-dioxide

314 1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)azetidine-3-carbonitrile

315 1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3- (trifluoromethyl)azetidin-3-ol

316 5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2- amine hydrochloride

317 2-(((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)methyl)quinazolin- 4(3H)-one

318 1-(3-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)propyl)-1H- benzo[d]imidazol-2(3H)-one

319 5-(2′-{[3-(Cyclohexylsulfonyl)propyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine

320 5-{3-Fluoro-2-[(1-methyl-1H-benzimidazol-2-yl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine

321 5-(2′-{[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]sulfonyl}-3-fluorobiphenyl-4- yl)pyrimidin-2-amine

322 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

323 5-[3-fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2- amine

324 4-{[4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2- yl]sulfonyl}piperazin-2-one

325 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide

326 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2- sulfonamide

327 4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

328 5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4- yl}pyrimidin-2-amine

329 5-{2′-[(5-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine formate salt

330 5-{2′-[(4-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine formate salt

331 5-{2′-[(5-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine formate salt

332 5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amine hydrochloride

333 5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amine hydrochloride

334 5-{2′-[(6-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine formate salt

335 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amine formate salt

336 5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine formate salt

337 5-{2′-[(5-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine hydrochloride

338 5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl- 4-yl]pyrimidin-2-amineformate salt

339 5-{2′-[(5-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine hydrochloride

340 5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl- 4-yl]pyrimidin-2-amine

341 5-(3-Fluoro-2′-(methylsulfonyly[1,1′-biphenyl]- 4-yl)pyridin-2-amine

342 4′-(6-aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

343 4′-(6-aminopyridin-3-yl)-N,N-diethyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

344 5-(3-fluoro-2′-(pyrrolidin-1-ylsulfonyly[1,1′-biphenyl]-4-yl)pyridin-2-amine

345 5-(3-fluoro-2′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

346 4′-(6-aminopyridin-3-yl)-N-cyclohexyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

347 (S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

348 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-isobutyl-[1,1′-biphenyl]-2-sulfonamide

349 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(tert-pentyl)-[1,1′-biphenyl]-2-sulfonamide

350 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-biphenyl]- 2-sulfonamide

351 (S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-phenylethyl)-[1,1′-biphenyl]-2- sulfonamide

352 (R)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

353 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-methylcyclobutyl)-[1,1′-biphenyl]-2- sulfonamide

354 4-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine 1,1- dioxide

355 (S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoropropan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

356 5-(2′-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine

357 tert-butyl 3-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate

358 4′-(6-aminopyridin-3-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2- sulfonamide

359 2-(1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)ethanol

360 1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-ol

361 (1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)methanol

362 3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2- sulfonamide

363 3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2- sulfonamide

364 3′-Fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2- sulfonamide

365 5[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine

366 3′-Fluoro-N-(2-hydroxyethyl)-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2- sulfonamide

367 N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

368 3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5- yl)biphenyl-2-sulfonamide

369 N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]methanesulfonamide

370 3′-Fluoro-N,N-dimethyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

371 N-tert-Butyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

372 2-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3- b]pyrazine

373 N,N-Diethyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

374 2-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

375 2-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3- b]pyrazine

376 3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)N--N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2- sulfonamide

377 2-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

378 3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2- sulfonamide

379 3′-Fluoro-N-methyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

380 3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2- sulfonamide

381 1-{[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-amine

382 2-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-5H-pyrrolo[2,3- b]pyrazine

383 2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

384 2-[2′-(Ethylsulfanyl)-3-fluorobiphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

385 7-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

386 7-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

387 4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide

388 4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1- methylethyl]biphenyl-2-sulfonamide

389 1-{[4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2- yl]sulfonyl}piperidin-4-amine

390 4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1- methylethyl]biphenyl-2-sulfonamide

391 4′-4-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N,N-diethyl-3′-fluorobiphenyl-2- sulfonamide

392 7-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

393 N-tert-Butyl-4′-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2- sulfonamide

394 2-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]-5-(trifluoromethyl)pyridin-3-yl}phenyl)-5H- pyrrolo[2,3-b]pyrazine

395 5-(2-Fluoro-4-{2-[(1- methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine

396 5-(2-Fluoro-4-{2-[(1- methylethyl)sulfanyl]pyridin-3-yl}phenyl)pyrazin-2-amine

397 2-{2-Fluoro-4-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

398 2-{2-Fluoro-4-[2-(2-methylpropoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

399 2-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

400 2-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}-5H-pyrrolo[2,3-b]pyrazine

401 5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrazin-2-amine

402 5-{4-[2-(Cyclopentyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

403 5-{4-[2-(Cyclohexyloxy)pyridin-3-yl]-2- fluorophenyl}pyrazin-2-amine

404 5-[2-Fluoro-4-(2-methoxypyridin-3- yl)phenyl]pyrazin-2-amine

405 5-{4-[2-(Cyclobutyloxy)pyridin-3-yl]-2- fluorophenyl}pyrazin-2-amine

406 tert-Butyl 3-[({3-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2- yl}oxy)methyl]pyrrolidine-1-carboxylate

407 5-{2-Fluoro-4-[2-(pyrrolidin-3-ylmethoxy)pyridin-3-yl]phenyl}pyrazin-2- amine

408 5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrimidin-2-amine

409 5-[4-(2-Aminopyridin-3-yl)-2- fluorophenyl]pyrimidin-2-amine

410 4′-(5-amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2- sulfonamide

411 3-Amino-6-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile

412 4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2- sulfonamide

413 4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

414 3-Amino-6-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazine-2- carbonitrile

415 4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide

416 3-Amino-6-[3-fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazine-2- carbonitrile

417 4′-(6-Aminopyridazin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

418 N-tert-Butyl-3′-fluoro-4′-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)biphenyl-2-sulfonamide

419 N-tert-Butyl-3′-fluoro-4′-(1,8-naphthyridin-3-yl)biphenyl-2-sulfonamide

420 N-tert-Butyl-3′-fluoro-4′-quinoxalin-6- ylbiphenyl-2-sulfonamide

421 N-tert-Butyl-3′-fluoro-4′-(1H-indol-5- yl)biphenyl-2-sulfonamide

422 4′-(1H-Benzimidazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

423 4′-(1H-Benzimidazol-5-yl)-3′-fluoro-N- methylbiphenyl-2-sulfonamide

424 4′-(1,3-Benzothiazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

425 N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[3,2-b]pyridin-6-yl)biphenyl-2-sulfonamide

426 3′-Fluoro-N-methyl-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

427 4′-(5-Aminopyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

428 N-tert-Butyl-4′-(5,6-diaminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

429 N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2- sulfonamide

430 4′-(6-Amino-5-fluoropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

431 N-tert-Butyl-4′-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′-fluorobiphenyl-2-sulfonamide

432 N-tert-Butyl-3′-fluoro-4′-(3H-imidazo[4,5-b]pyridin-6-yl)biphenyl-2-sulfonamide

433 4′-(5-Amino-6-methoxypyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

434 4′-(5-Amino-6-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

435 4′-(5-Amino-3-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

436 4′-(6-Amino-4-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

437 4′-(6-amino-2-cyanopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

438 4′-(5-amino-1,3,4-thiadiazol-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

439 (R)-4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2- sulfonamide

440 4-((4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine 1,1-dioxide

441 4′-(5-Amino-6-chloropyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

442 4′-(5-Amino-6-bromopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

443 6-amino-3-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)picolinonitrile

444 N-tert-Butyl-3′-fluoro-4′-[1,2,4]triazolo[4,3-a]pyridin-7-ylbiphenyl-2-sulfonamide

445 4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

446 4′-(5-Amino-6-methylpyrazin-2-yl)-3′- fluorobiphenyl-2-sulfonamide

447 N-tert-Butyl-3′-fluoro-4′-(1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide

448 N-tert-Butyl-4′-(5,6-diaminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide

449 4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide

450 4′-(6-Amino-5-cyanopyridin-3-yl)--N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

451 4′-(6-Amino-5-chloropyridin-3-yl)--N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

452 4′-[6-Amino-5-trifluoromethyl-pyrridin-3-yl]--N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

453 4′-[2-Amino-4-(trifluoromethyl)pyrimidin-5-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

454 4′-(2-Amino-4-methylpyrimidin-5-yl)--N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

455 N-tert-Butyl-3′-fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]biphenyl-2- sulfonamide

456 4′-(7-Amino-1H-indol-5-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2- sulfonamide

457 3′-Fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-methylbiphenyl-2- sulfonamide

458 4′-(7-Amino-1H-indol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

459 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]acetamide

460 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]urea

461 5-[2,3-Difluoro-2′-(methylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

462 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide

463 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methylbiphenyl-2-yl]methanesulfonamide

464 4′-(5-Aminopyrazin-2-yl)-2′,3′- difluorobiphenyl-2-sulfonamide

465 4′-(2-Aminopyrimidin-5-yl)-2′,3′-difluoro-N-methylbiphenyl-2-sulfonamide trifluoroacetic acid salt

466 4′-(2-Aminopyrimidin-5-yl)--N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide trifluoroacetic acid salt

467 5-[2′,3-Difluoro-4′-(trifluoromethoxy)biphenyl- 4-yl]pyrazin-2-amine

468 5-(2′,3-Difluorobiphenyl-4-yl)pyrazin-2-amine

469 5-(2′-Chloro-3-fluorobiphenyl-4-yl)pyrazin-2- amine

470 5-(3-Fluoro-2′-methylbiphenyl-4-yl)pyrazin-2- amine

471 5-[2′,3-Difluoro-4′-(trifluoromethyl)biphenyl-4- yl]pyrazin-2-amine

472 5-[3-Fluoro-2′-(trifluoromethyl)biphenyl-4- yl]pyrazin-2-amine

473 5-(3-Fluoro-2′-methoxybiphenyl-4-yl)pyrazin- 2-amine

474 5-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4- yl]pyrazin-2-amine

475 5-[3-Fluoro-2′-(trifluoromethoxy)biphenyl-4- yl]pyrazin-2-amine

476 4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-ol

477 5-[3-Fluoro-2′-(phenylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

478 5-(2′,3,6′-Trifluorobiphenyl-4-yl)pyrazin-2- amine

479 N-(4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]benzenesulfonamide

480 5-(2′-Ethyl-3-fluorobiphenyl-4-yl)pyrazin-2- amine

481 {[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2- yl]oxy}acetic acid

482 5-[3-Fluoro-2′-(1-methylethyl)biphenyl-4- yl]pyrazin-2-amine

483 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]ethanone

484 5-[3-Fluoro-2′-(2,2,2-trifluoroethoxy)biphenyl- 4-yl]pyrazin-2-amine

485 4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2- carboxylic acid

486 4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2- carboxamide

487 5-[3-Fluoro-2′-(1-methylethoxy)biphenyl-4- yl]pyrazin-2-amine

488 5-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

489 2-[3,4′-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

490 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonmide

491 N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]ethanesulfonamide

492 N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2- yl)biphenyl-2-yl]N--N-methylmethanesulfonamide

493 N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylethanesulfonamide

494 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylethanesulfonamide

495 N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-2-methylpropane-1- sulfonamide

496 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamide

497 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,2-dimethylpropane-1-sulfonamide

498 5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-1H-pyrrolo[2,3- b]pyridine

499 5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrimidin-2-amine

500 2-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-5H-pyrrolo[2,3- to]pyrazine

501 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-carboxamide

502 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-carboxamide

503 4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-carboxamide

504 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- carboxamide

505 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- carboxamide

506 5-[3-Fluoro-2′-(piperazin-1-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine

507 5-{2′-[(4-Acetylpiperazin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

508 4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-carboxamide

509 5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2- amine

510 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N- methylbiphenyl-2-carboxamide

511 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- carboxamide

512 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2- carboxamide

513 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2- carboxamide

514 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-4-ol

515 5-{2′-[(4-Aminopiperidin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

516 5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2- amine

517 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2- carboxamide

518 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2- carboxamide

519 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one

520 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one

521 5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

522 5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2- amine

523 4-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-2-amine

524 2-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-4-amine

525 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine

526 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4- yl]pyrazin-2-amine

527 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4- yl]pyrimidin-2-amine

528 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine

529 5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

530 6-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-2- carbonitrile

531 2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-3- carbonitrile

532 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile

533 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine

534 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine

535 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine

536 5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

537 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

538 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

539 5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

540 5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

541 5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

542 5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine

543 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4- yl]-1H-benzimidazole

544 6-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-3H-imidazo[4,5-b]pyridine

545 5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

546 5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine

547 5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine

548 5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine

549 5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

550 5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine

551 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

552 5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2- amine

553 5-[3-Fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

554 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4- (trifluoromethyl)biphenyl-2-ol

555 4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2- amine

556 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-4- amine

557 5-[3-Fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]methoxy}biphenyl-4- yl]pyrimidin-2-amine

558 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol

559 5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2- amine

560 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2- amine

561 5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2- amine

562 5-[3-Fluoro-2′,4′-bis(trifluoromethyl)biphenyl- 4-yl]pyrazin-2-amine

563 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbonitrile

564 5-{5-[2-(Pyrimidin-2-yloxy)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin- 2-amine

565 4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-5-(trifluoromethyl)phenoxy}pyrimidin-2-amine

566 5-{5-[2-(Pyrimidin-2-yloxy)phenyl]pyridin-2- yl}pyrimidin-2-amine

567 4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenoxy}pyrimidin-2-amine

568 5-(5-{2-[(4-Aminopyrimidin-2-yl)oxy]phenyl}pyridin-2-yl)pyrimidin-2-amine

569 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methylbiphenyl-2-sulfonamide

570 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methoxybiphenyl-2-sulfonamide

571 4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl- 2-sulfonamide

572 4′-(5-Aminopyrazin-2-yl)-N,N- dimethylbiphenyl-2-sulfonamide

573 5-[2′-(Morphonlin-4-ylsulfonyl)biphenyl-4- yl]pyrazin-2-amine

574 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′-fluorobiphenyl-2-sulfonamide

575 4′-(5-Aminopyrazin-2-yl)-2′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide

576 4′-(2-Amino-1,3-oxazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

577 4′-(2-Amino-1,3-thiazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

578 4′-(2-Amino-1,3-thiazol-4-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide

579 4-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-1,3-thiazol-2-amine

580 N-tert-Butyl-3′-fluoro-4′-(8-fluoroimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide

581 4′-(5-Aminoimidazo[1,2-a]pyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

582 2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide

583 2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide

584 N-tert-Butyl-4′-(5-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

585 N-tert-Butyl-4′-(6-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

586 N-tert-Butyl-3′-fluoro-4′-[6(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl]biphenyl-2-sulfonamide

587 Ethyl 2-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-5- carboxylate

588 N-tert-Butyl-3′-fluoro-4′-(5-methoxyimidazo[1,2-a]pyridin-2-yl)biphenyl-2- sulfonamide

589 5-[2′-Methylsulfonyl)biphenyl-4-yl]pyrazin-2- amine.

590 5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4- yl]pyrazin-2-amine.

591 4′-(5-Aminopyrazin-2-yl)-N,N,3′- trimethylbiphenyl-2-sulfonamide.

592 4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl- 2-sulfonamide.

593 N-[4′-(5-Aminopyrazin-2-yl)biphenyl-2- yl]methanesulfonamide.

594 4′-(5-Aminopyrazin-2-yl)biphenyl-2- sulfonamide.

595 N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-sulfonamide.

596 N-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2- sulfonamide.

597 4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide.

598 3-Amino-6-[2′-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylic acid.

599 2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide.

600 2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N- diethylacetamide.

601 5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2- amine.

602 5,5′-(3,3″-Difluoro-1,1′:2′,1″-terphenyl-4,4″-diyl)dipyrazin-2-amine.

603 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylic acid.

604 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde.

605 5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine.

606 5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2- amine.

607 2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2- yl]methyl}amino)ethanol.

608 5-{2-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.

609 5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

610 5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.

611 5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.

612 5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.

613 5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.

614 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine.

615 5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

616 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine.

617 5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

618 6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile.

619 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile.

620 5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.

621 5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

622 5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

623 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-2-methylpyrimidin-4-amine.

624 5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine.

625 5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine.

626 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile.

627 6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile.

628 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]oxy}ethanol.

629 2-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]oxy}ethanol.

630 5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4- yl]pyrazin-2-amine.

631 5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4- yl]pyrimidin-2-amine.

632 5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine.

633 5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine.

634 5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine.

635 5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine.

636 5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.

637 5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

638 5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine.

639 5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine.

640 5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4- yl]pyrazin-2-amine.

641 5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4- yl]pyrimidin-2-amine.

642 {[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2- yl]oxy}acetonitrile.

643 {[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile.

644 {[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl- 2-yl]oxy}aceticacid.

645 5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine.

646 5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine.

647 5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin- 2-amine.

648 5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin- 2-amine.

649 2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol.

650 2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol.

651 5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine.

652 5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine formic acid salt.

653 5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine.

654 5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine.

655 (2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.

656 (2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.

657 (2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.

658 (2I)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol.

659 N-(4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanesulfonamide

660 5-(3-Fluoro-2′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

661 4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide

662 4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′- biphenyl]-2-sulfonamidetrifluoroacetate

663 5-(2′-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine

664 4′-(6-Aminopyrazin-2-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2- sulfonamide

665 4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]- 2-sulfonamide

666 4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl- [1,1′-biphenyl]-2-sulfonamide

667 4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′- biphenyl]-2-sulfonamide

668 (racemic)-1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2- yl)sulfonyl)piperidin-3-ol

669 4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide

670 N-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4- yl)acetamide

671 2-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pipendin-3- yl)ethanol.

672 1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pipendin-3- yl)methanol.

673 2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3- yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide.

674 2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3- yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide.

675 2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide.

676 5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin- 2-amine.

677 5-{5-[2-(Morpholin-4- ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine.

678 5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin- 2-amine.

679 5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2- amine trifluoroacetic acidsalt.

680 5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2- amine trifluoroacetic acidsalt.

681 5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2- yl}pyrimidin-2-aminetrifluoroacetic acid salt.

682 5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2- amine trifluoroacetic acidsalt.

683 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N- ethylbenzenesulfonamidetrifluoroacetic acid salt.

684 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamide trifluoroacetic acid salt.

685 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1- methylethyl]benzenesulfonamide trifluoroaceticacid salt.

686 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1- methylethyl]benzenesulfonamide trifluoroaceticacid salt.

687 4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulfonyl)piperazin-2-one.

688 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide.

689 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide.

690 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2- hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide.

691 5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2- yl}pyrimidin-2-aminetrifluoroacetic acid salt.

692 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide trifluoroacetic acid salt.

693 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide.

694 2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N- [(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide.

695 3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile trifluoroacetic acid salt.

696 5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin- 2-amine.

697 5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H- pyrrolo[2,3-b]pyridine.

698 5-(3-fluoro-2-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine.

699 5-(2′,3,4′-Trifluorobiphenyl-4- yl)pyrazin-2-amine

700 racemic 5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine

701 4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-carbonitrile

702 1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)imidazolidin-2-one

703 4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

704 6-Amino-3-{2′-[(1,1- dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile

705 1-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide

706 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2- sulfonamide

707 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2- sulfonamide

708 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2- sulfonamide

709 1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidine- 4-carboxamide

710 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′- fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

711 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′- fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

712 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′- fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide

713 4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)-[1,1′- biphenyl]-2-sulfonamide

714 4′-(5-Amino-3-cyanopyrazin-2-yl)-3′- fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide

715 6-Amino-3-{3-fluoro-2′-[(3- oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2- carbonitrile

716 N-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide

717 1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3- dimethylbutan-2-one

718 5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

719 5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

720 5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

721 5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2- amine

722 5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2- amine

723 5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

724 4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine

725 5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

726 6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine

727 2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine

728 5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

729 6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile

730 1-{[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile

731 1-{[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide

732 2-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile

733 2-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide

734 5-{2′-[(2-Amino-1,1- dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

735 2-{[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile

736 2-{[4′-(5-Aminopyrazin-2-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide

737 5-{2′-[(2-Amino-1,1- dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

738 1-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile

739 1-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide

740 5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine

741 5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine

742 5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

743 5-(3-Fluoro-2′-(pyrimidin-4-ylthio)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

744 5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

745 6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile

746 6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2- carbonitrile

747 6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrile

748 N-(tert-Butyl)-3′-fluoro-4′-(5-(methylsulfonamido)pyrazin-2-yl)-[1,1′- biphenyl]-2-sulfonamide

749 5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl- 4-yl}pyrazin-2-aminehydrogen chloride salt

750 5-{3-Fluoro-2′- [(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine

751 5-(3-Fluoro-2′-{[(1- methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine

752 5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2- amine

753 2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin- 4-amine

754 racemic 5-(3-Fluoro-2′-{[2- (trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

755 1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol

756 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2- carboxamide

757 5-{2′-[(1,1-Dioxidothiomorpholin-4- yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine

758 1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2- yl)ethanol(diastereomericmixture).

759 1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2- yl)ethanol(diastereomericmixture).

760 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide

761 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide

762 (3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol

763 (cis/trans) 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2- carboxamide

764 (3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pipendin-3-ol

765 (cis/trans) 4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2- carboxamide

766 racemic 5-(3-Fluoro-2′-{[2- (trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

767 (3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pipendin-3-ol

768 (3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pipendin- 3-ol

769 (3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

770 (3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

771 (3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

772 (3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

773 5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine (diastereoisomeric mixture).

774 5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

775 5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

776 5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

777 5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

778 5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

779 5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

780 5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine (diastereoisomeric mixture)

781 5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3- b]pyridine

782 5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2- amine

783 5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2- amine

784 2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide

785 2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-5- (trifluoromethyl)benzamide

786 2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5- (trifluoromethyl)benzamide

787 2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1- methyl-ethyl]benzamide

788 2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1- methyl-ethyl]benzamide

789 2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1- methyl-ethyl]benzamide

790 2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1- methyl-ethyl]benzamide

791 [2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-(3-hydroxyazetidin-l- yl)methanone

792 [2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl[4-(methylamino)-1- piperidyl]methanone

793 [2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(1,1-dioxo-1,4- thiazinan-4-yl)methanone

794 2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide

795 [2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1- piperidyl)methanone

796 [2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1- piperidyl)methanone

797 2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tetrahydropyran-4-yl-benzamide

798 [2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin- 4-yl]methanone

799 racemic [2-[4-(2-Aminopyrimidin-5-yl)-3- fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone

800 N-{3-[4-(2-Aminopyrimidin-5-yl)-3- fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide

801 N-{3-[4-(5-Aminopyrazin-2-yl)-3- fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide

802 N-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2- dimethylpropanamide

803 racemic 5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrazin-2-amine hydrochloride

804 5-(2-Fluoro-4-(2-(pyrrolidin-3- ylsulfonyl)pyridin-3-yl)phenyl)pyrimidin-2-amine formic acid salt.

805 5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amine hydrochloride.

806 5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amine hydrochloride

807 5-(4-(2-(Cyclohexlsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amine hydrochloride

808 5-(4-(2-(Cyclohexylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amine hydrochloride

809 5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidine-2-amine hydrochloride

810 5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amine hydrochloride

811 5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amine formic acid salt.

812 5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amine formic acid salt.

813 racemic 5-(4-(2-(sec- Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amine formate

814 racemic 5-(4-(2-(sec- Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amine formate

815 1-((3-(4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1- yl)ethanone

816 1-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1- yl)ethanone hydrogenchloride salt

817 5-(2-Fluoro-4-(2-((3- methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-amine hydrogen chloride salt.

818 5-(2-Fluoro-4-(2-((3- methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-amine hydrogen chloride salt.

819 4-((3-(4-(2-aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro- 2H-thiopyran 1,1-dioxide

820 4-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro- 2H-thiopyran 1,1-dioxide

821 5-(2-Fluoro-4-(2-((2- morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-amine formic acid salt.

822 5-(2-Fluoro-4-(2-((2- morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-amine

823 5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3- yl)pyrimidin-2-amine formic acidsalt.

824 5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3- yl)pyrazin-2-amine formic acidsalt.

825 5-(2-Fluoro-4-{2-[(1- methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine

826 5-(2-Fluoro-4-(2- (isopropylsulfonyl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine

827 5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine formic acid salt.

828 5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine formic acid salt.

829 5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine formic acid salt.

830 5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine hydrochloride

831 5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2- amine formic acid salt.

832 5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine hydrochloride

833 5-(2,3-Difluorobiphenyl-4-yl)pyrazin-2-amine.

834 5-(3-Fluoro-2-methoxybiphenyl-4-yl)pyrazin-2- amine.

835 5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine.

836 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2-methoxybiphenyl-2-sulfonamide.

837 N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide.

838 5-(3-Fluoro-2′-(pyrazin-2-yl)-[1,1′-biphenyl]-4- yl)pyrazin-2-amine

839 5-(3-Fluoro-2′-pyrazin-2-ylbiphenyl-4- yl)pyrimidin-2-amine.

840 5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrazin-2- amine.

841 5-[2′-(5-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine.

842 5-[2′-(6-Aminopyrazin-2-yl)-3-fluorobiphenyl- 4-yl]pyrazin-2-amine.

843 5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidin-2-amine.

844 5,5′-(3′-Fluorobiphenyl-2,4′-diyl)clipyrimidin-2- amine.

845 5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2- amine.

846 5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine.

847 5-[3-Fluoro-2′-(1-methyl-1H-pyrazol-4-yl)biphenyl-4-yl]pyrazin-2-amine.

848 5-(3-Fluoro-2′-pyrimidin-5-ylbiphenyl-4- yl)pyrazin-2-amine.

849 5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidine-2-carbonitrile.

850 5-[3-Fluoro-2′-(2-morpholin-4-ylpyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine.

851 1-{4-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1H-pyrazol-1-yl}-2- methylpropan-2-ol.

852 5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2- amine.

853 5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2- amine.

854 5-{2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]phenyl}pyrimidin-2-amine.

855 5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine.

856 5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

857 5-[2′-(1,1-Dioxido-1,2-thiazinan-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

858 5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine

859 5-[2-Fluoro-4-(2-pyrrolidin-1-ylpyridin-3- yl)phenyl]pyrazin-2-amine

860 1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl- 2-yl]pyrrolidin-2-oneC) Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Scheme A described suggested syntheticroutes. Using the schemes, the guidelines below, and the examples, aperson of skill in the art may develop analogous or similar methods fora given compound that is within the invention. These methods arerepresentative of the synthetic schemes, but are not to be construed aslimiting the scope of the invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemic andscalemic mixtures, diastereomers, geometric isomers, and enantiomersthereof are encompassed within the scope of the present invention.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes are offered by way of illustration; theinvention should not be construed as being limited by the chemicalreactions and conditions expressed. The methods for preparing thevarious starting materials used in the schemes and examples are wellwithin the skill of persons versed in the art. No attempt has been madeto optimize the yields obtained in any of the example reactions. Oneskilled in the art would know how to increase such yields throughroutine variations in reaction times, temperatures, solvents and/orreagents.

General: ¹H and ¹³C NMR spectra were measured on a Bruker AC-300 (300MHz) spectrometer using tetramethylsilane and the deuterated solventrespectively as internal standards. Elemental analyses were obtained byQuantitative Technologies Inc. (Whitehouse, N.J.) and the results werewithin 0.4% of the calculated values unless otherwise mentioned. Meltingpoints were determined in open capillary tubes with a MeI-Temp IIapparatus (Laboratory Devices Inc.) and were uncorrected. Electrospraymass spectra (MS-ESI) were recorded in the positive mode on a HewlettPackard 59987A spectrometer. High resolution mass spectra (HRMS) wereobtained on a Micromass Autospec. E spectrometer by fast atombombardment (FAB) technique.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Scheme A-G,Intermediates A-HZ, Examples 1-860 and prophetic Examples 1-13.Compounds analogous to the target compounds of these examples can bemade according to similar routes. The disclosed compounds are useful aspharmaceutical agents as described herein.

Abbreviations or acronyms useful herein include:

Abbreviation Meaning BOC/boc tert-butyloxycarbonyl BOPbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateCpd compound DCE dichloroethane DCM dichloromethane DIPEA diisopropylethyl amine DMA N,N-dimethylacetamide DMAP N,N-dimethylaminopyridine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide DPBS Dulbecco's phosphatebuffered saline EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride ESI electrospray ionization Et₃N or TEA triethylamineEtOAc ethyl acetate h/hr/hrs hour(s) HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate HOBT 1-hydroxybenzotriazole hydrate HBTUO-benzotriazol-1-yloxy-N,N,N′,N′-tetramethyluronium hexafluorophosphateI.D. interior diameter LG Leaving group LiOH lithium hydroxide m-CPBAmeta-chloroperoxybenzoic acid min minute(s) MS mass spectroscopy NMRnuclear magnetic resonance spectroscopy OTf Triflate PG protecting groupRT/rt room temperature TBME tert-butyl methyl ether THF tetrahydrofuranTLC thin layer chromatography Tos p-toluenesulfonylGeneral Guidance

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art. The substituents forcompounds of Formula (I) or a form thereof, represented in the schemesbelow, are as previously defined herein.

Unless otherwise specified, reaction solutions were stirred at roomtemperature under a N_(2(g)) or Ar_((g)) atmosphere. When solutions were“concentrated to dryness”, they were concentrated using a rotaryevaporator under reduced pressure, when solutions were dried, they aretypically dried over a drying agent such as MgSO₄ or Na₂SO₄.

Normal phase flash column chromatography (FCC) was performed on silicagel with RediSep® silica gel columns using ethyl acetate(EtOAc)/hexanes, CH₂Cl₂/MeOH, CH₂Cl₂/10% 2 N NH₃ in MeOH, CH₂Cl₂/1-PrOH,and the like as eluent, unless otherwise indicated.

Reverse phase high performance liquid chromatography (HPLC) wasperformed under the following conditions: 1) Instrument, Shimadzu;Column, Waters XBridge C18 10 μm (250×50 mm), Phenomenex Gemini column 5μm C18 (150×21.2 mm) or Waters Xterra RP18 OBD 5 μm (100×30 mm);Gradient, 95:5 to 0:100 water (0.05% trifluoroacetic acid (TFA))/CH₃CN(0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ=220-254 nM; 2)Instrument, Gilson; Column, Phenomenex LUNA column 5 μm C18 (250×50 mm)or Waters XBridge Prep C18 OBD 5 μm (30×150 mm); Gradient, 95:5 to 0:100water (0.05% TFA)/CH₃CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection,UV at λ=220-254 nM; 3) Instrument, Gilson/Shimadzu: Column, InertsilODS-3 column (30×100 mm) or Inertsil ODS-3 (30×50 mm, 5 μm); Gradient,water-acetonitrile with both phases with 0.05% by volume trifluoroaceticacid; 1 min hold at 5% ACN, then 6 min gradient to 99% ACN followed by ahold at that concentration for 3 min. Flow rate, 80 ml/min; heatedcolumn at 46° Celsius with detection of UV light at λ=254 nm; and 4)Instrument, Dionex: UVD 170U Diode array detector and ThermoFinneganSurveyor MSQ plus mass spectrometer for data collection. Waters XBridgeC18 5 μm OBD 50×100 mm prep column.

All runs on the Dionex utilized water acetonitrile with 20 mM NH₄OHadded to the aqueous phase and a flow rate for all gradients was 80mL/min using four possible gradients: 1) 5-60% MeCN over 12 min, thenramped to 100% MeCN and held for 6.3 min; 2) 30-70% MeCN over 12 min,then ramped to 100% MeCN and held for 6.3 min; 3) 50-80% MeCN over 12min, then ramped to 100% MeCN and held for 6.3 min; and 4) 60-100% MeCNover 12 min, and then held for 6.3 min. The total run time for allgradient systems was 18.5 min.

Instances where solutions were filtered through a syringe filter, Pall0.45 μM GHP membrane 13 mm and 25 mm diameter syringe filters were used

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone. Microwave reactions were carried out ineither a CEM Discover™ or a Biotage Initiator™ or Optimizer™ Microwaveat specified temperatures. Mass spectra were obtained on an Agilentseries 1100 MSD using electrospray ionization (ESI) in positive modeunless otherwise indicated. Calculated mass corresponds to the exactmass.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz),DPX500 (500 MHz), DRX 600 (600 MHz) spectrometer. The format of the ¹HNMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Hydrochloride salts were obtained by treating the corresponding freebases with HCl (4 N in dioxane, 2 M in Et₂O, or 1.25 N in MeOH) at roomtemperature with mixtures either concentrated to obtain the HCl salt, orthe resulting solid being isolated by filtration. Trifluoroacetic acidsalts were obtained by purification of the crude reaction product bypreparative reverse phase HPLC, whereby the final products were isolatedas either mono-, di- or tri-fluoro acetic acid salts.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced Chemistry).

The compounds of Formula (I), wherein ring A, L, V, W, R, R′, n, R₁, R₂,R₃, and R₄ are defined as in Formula (I), may be synthesized as outlinedby the general synthetic route illustrated in Scheme A-G.

Referring to Scheme A, compounds of formulae (XI) can be obtainedthrough a series of metal mediated cross coupling reactions startingfrom compound (XIII). Compounds of formulae (XIV) in which Ar¹ can be anamine substituted or des-amino 5-, 6-membered or 5/6- or 6/6-fusedaromatic or heteroaromatic nitrogen containing ring system, can beprepared via Pd mediated cross coupling of either an aryl or heteroarylboronic acid or ester, Ar¹—B(OP)₂, with intermediates of structure(XIII) in which W is bromo or chloro, Y is an alkyl, hetero-alkyl, aryl,or heteroaryl and Z is H, fluoro, alkyl or heteroalkyl. In instanceswhere W is either bromo or chloro, the boronic acid or ester of compound(XIII) can be formed via palladium catalysis usingbis(pinacolato)diboron and KOAc in the presence of[1,1′-bis(diphenylphosphino)ferrocene]-dichloro-palladium(II).CH₂Cl₂(Pd(dppf)Cl₂.CH₂Cl₂) or the X-Phos pre-catalyst in solvents such as1,4-dioxane or DMSO, at temperatures ranging from 0-100° Celsius.Alternatively, compounds of Formulae (XIII) in which W is B(OP)₂ can becross-coupled with an aryl or heteroaryl halide, Ar¹—X where X is eitherbromo or chloro to obtain compounds of formulae (XII). Preferably, incompounds of formulae (XII), Y is t-butyl, cyclobutyl, trifluoromethoxy,or SF₅, Z is H or -fluoro ortho to Ar¹, and Ar¹ is eitheramino-pyrazine, amino-pyrimidine, or amino-pyridine alternativelysubstituted with or without CN, CH₃, OCH₃, CF₃, Cl, F, OH, and NH₂.Preferred solvents for cross coupling reactions include DME, DMSO,1,4-dioxane, THF, EtOH DMF, water, and toluene or mixtures thereof, inthe presence of a base, such as Na₂CO₃, K₂CO₃, KOAc, KH₂PO₄, and K₃PO₄using catalysts such as Pd(dppf)Cl₂.CH₂Cl₂, palladium trifluoroacetateand PhP₃,chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]-palladium(II),1,1′-bis[di-t-butylphosphino)ferrocene]palladium chloride withtemperatures ranging from rt to 100° Celsius.

Compounds of formulae (XI) can be prepared from compounds of formulae(XIII) via sequential (XIII→XIV→XI or XIII→XV→XI) Pd mediatedcross-coupling using methods and intermediates, analogous to thosedescribed above compounds of formulae (XV) can be obtained via compoundsof formulae (XIII), wherein Y is a boronic acid or ester and W is bromoor chloro, Compounds of formulae (XIII) in which Y is the boronic acidor ester can be obtained from the corresponding iodide wherein W iseither bromo or chloro. Preferred methods for conversion of the iodo tothe corresponding boronic acid or ester are analogous to the methodsdescribed above. In some cases, aryl and heteroaryl halides, boronicesters and acids are commercially available or can be prepared by knownmethods.

Compounds (XIV) in which Y is alkyl or cycloalykyl can be obtained fromthe corresponding bromide using alkylzinc bromides in solvents such asTHF in the presence of palladium acetate and2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl at temperaturesranging from rt to 100° Celsius.

In further embodiments, compounds of formulae (XI) containing a pyridinecore, where Z is H or -fluoro ortho to Ar¹, can be prepared usinganalogous Pd mediated cross coupling reactions described herein.

Referring to Scheme B, substituted aryl and heteroaryl sulfonamides(XVI) possessing from 0 to 3 G groups, where a G group is alkyl,cycloalkyl, heteroalkyl, CF₃, F, Cl, Br, or combinations thereof, andwhere X is bromo or chloro, can be prepared by addition of variousprimary and secondary amines to the aryl or heteroaryl sulfonyl chloridein solvents such as CH₂Cl₂, CH₃CN, THF, and DMF in the presences ofbases such as pyridine, Et₃N and i-Pr₂EtNH at temperatures ranging from−20° to 100° Celsius.

Alternatively, sulfones (XVI) can be obtained from the correspondingbromo or chloro aryl thiol (XVIII). S_(N)1 substitution in the presenceof a strong acid, such as H₂SO₄, with an appropriately reactive alcohol,such as tert-butanol, provides the desired aryl sulfide. Additionally,one can obtain substituted aryl sulfides via S_(N)2 or S_(N)Ardisplacement of alkyl or aryl bromide, chloride, and fluorides (arylonly) under basic conditions using bases such as NaH or i-Pr₂EtNH andthe desired in solvents such as THF, DMSO, and DMF at temperaturesranging from rt to 100° Celsius. Sulfone (XVI) can then be obtained viaoxidation of the sulfide using an appropriate oxidant such as m-CPBA,oxone, or RuCl₃/NaIO₄.

Referring to Scheme C, sulfonamides of formulae (XIX) can be preparedfrom an aniline (XX) possessing from 0 to 3 G groups G, where a G groupcan be a variety of alkyl, heteroalkyl, F, Cl, Br, CF₃, or combinationsthereof, and X is bromo, chloro, B(OH)₂, or B(OP)₂, by treatment with anappropriate sulfonyl chloride on which R is alkyl, cycloalkyl,substituted aryl, substituted heteroaryl or CF₃, in a solvent, such asCH₂Cl₂, in the presence of a base, such as pyridine, at temperaturesranging from 0° to 100° Celsius.

Referring to Scheme D, methanesulfonamides of formulae (XXI) can beprepared by treatment of a substituted (halomethyl)benzene, where X isbromo or chloro and possessing 0 to 3 G groups, which can be a varietyof alkyl, cycloalkyl, heteroalkyl, F, Cl, Br, CF₃, or combinationsthereof, with sodium sulfite to provide the desired arylmethyl sulfonatewhich can be subsequently treated with phosphorous pentachloride toprovide the desired arylmethylsulfonyl chloride (XXIII). Sulfonylchlorides (XXIII) can then be transformed to the correspondingsulfonamide (XXI) using methods described herein.

Referring to Scheme E, variously substituted amides (XXIV) can beprepared using standard amide coupling reactions. Substituted carboxylicacid (XXV), where X is bromo or chloro, and possessing 0 to 3 G groups,which can be a variety of alkyl, cycloalkyl, heteroalkyl, F, Cl, Br,CF₃, or combinations thereof, can be treated with various primary andsecondary amines using standard carbodiimide peptide coupling reagents,such as HATU or EDCl, in solvents such as DMF and CH₂Cl₂, attemperatures ranging from 0-600 Celsius, to provide amide (XXIV).

Referring to Scheme F, phenyl ethers of formulae (XXVI) can be preparedfrom the corresponding phenol (XXVII), where X is bromo or chloro, andpossessing 0 to 3 G groups, which can be a variety of alkyl, cycloalkyl,heteroalkyl, F, Cl, Br, CF₃, or combinations thereof, and n=0.1.Treatment of phenol (XXVII) with appropriately substituted halo aromaticheterocycles, where halo refers to F, Cl, and Br, or halomethyl aromaticheterocycles in which halo refers to Cl or Br, a base, such as Cs₂CO₃,K₂CO₃, or Na₂CO₃. In a polar solvent, such as DMSO, CH₃CN, or DMF attemperatures ranging from rt to 100° Celsius, provides ethers (XXVI).

Referring to Scheme G, instances where Ar¹ in Scheme A is a 5-,6-membered, or 5/5-, 5/6-fused heterocyle, compounds of formulae(XXVIII) and (XXX) can be obtained starting from methyl ketone (XXIX).Treatment of the ketone with either urea or thiourea in the presence ofI₂ in EtOH at temperatures ranging from rt to 80° Celsius results in thecorresponding five-membered amino heterocycle (XXVIII). Whereas,treatment of the ketone under analogous conditions with substituted2-amino pyridines, possessing 0 to 3 G groups, which can be a variety ofalkyl, cycloalkyl, heteroalkyl, F, Cl, Br, CF₃, or combinations thereof,results in a substituted fused 5/6 heterocycle (XXX).

EXAMPLES

The following examples are offered by way of illustration; the inventionshould not be construed as being limited by the chemical reactions andconditions expressed.

5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineMethod 1

To a 250 mL round-bottomed flask were added a stirbar,5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (3.07 g, 11.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.82 g,22.9 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (512 mg, 0.623 mmol), and KOAc (2.30 g,23.4 mmol). The flask was then thoroughly sparged with nitrogen and thencharged with 1,4-dioxane (114 mL, sparged with N₂ for 30 min). The flaskwas then heated at 80° Celsius for 19.5 hours before cooling to rt,filtering the reaction mixture through Na₂SO₄ and concentrating thefiltrate to dryness. The residue was purified by FCC to give the titlecompound. MS (ESI): mass calcd. for C₁₆H₁₉BFN₃O₂, 315.16; m/z found,316.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (dd, J=2.4, 1.5, 1H),8.02 (d, J=1.5, 1H), 7.96-7.89 (m, 1H), 7.56 (dd, J=7.7, 1.1, 1H), 7.42(dd, J=11.8, 1.1, 1H), 6.77 (s, 2H), 1.31 (s, 12H).

Method 2 Step A: 5-(4-Bromo-2-fluorophenyl)pyrazin-2-amine

To a solution of 5-bromopyrazin-2-amine (1.74 g, 10.0 mmol) in1,4-dioxane (40 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.65 g,10.5 mmol) and KOAc (1.96 g, 20.0 mmol). The mixture was sparged with N₂several times before adding Pd(dppf)Cl₂.CH₂Cl₂ (0.41 g, 0.5 mmol). Theresultant mixture was stirred at 90° Celsius for 60 hours under N₂.After cooling to rt, 4-bromo-2-fluoro-1-iodobenzene (4.5 g, 15.0 mmol),K₂CO₃ (2.76 g, 20.0 mmol) and another portion of Pd(dppf)Cl₂.CH₂Cl₂(0.41 g, 0.5 mmol) were added. The resultant mixture was sparged with N₂again, and stirred at 80° Celsius for 48 hours under N₂. The mixture wasthen cooled to rt, diluted with THF (30 mL) and filtered. The filtratewas concentrated to dryness and the residue purified by FCC to give5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (0.4 g, 15%). ¹H NMR (300 MHz,DMSO-d₆) δ 8.33 (s, 1H), 8.01 (s, 1H), 7.82 (m, 1H), 7.63 (dd, J=11.1,2.1, 1H), 7.50 (dd, J=8.4, 2.1, 1H), 6.75 (s, 2H).

Step B

To a solution of 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (535 mg, 2.0mmol) in 1,4-dioxane (20 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.1 g, 4.0mmol) and KOAc (0.39 g, 4.0 mmol). The mixture was sparged by bubblingN₂ for 10 min. The mixture was treated with Pd(dppf)Cl₂.CH₂Cl₂ (82 mg,0.1 mmol) and then stirred at 80° Celsius for 1 hour under N₂. Aftercooling to rt, the reaction mixture was filtered through Na₂SO₄ and thefiltrate concentrated to dryness. The residue was purified by FCC togive the title compound (460 mg, 72%).

6-Amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileStep A: 6-Amino-3-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile

To a 200 mL round-bottomed flask were added a stirbar,5-amino-3-cyano-2-bromopyrazine (4.09 g, 20.5 mmol),4-chloro-2-fluorophenylboronic acid (3.90 g, 22.4 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (839 mg, 1.03 mmol) and K₂CO₃ (8.36 g, 60.5 mmol).The flask was flushed with nitrogen and then charged with toluene (17.5mL), water (17.5 mL) and DMF (10.5 mL), all of which were sparged withN₂. The flask was heated at 80° Celsius for 19 hours before cooling tort and adding MgSO₄ until the mixture was a thick paste. The reactionmixture was then stirred with EtOAc and filtered through a thick pad ofcelite. The pad was rinsed with EtOAc until the filtrate was colorless.The filtrate was concentrated to dryness and subjected to FCC to give6-amino-3-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile. MS (ESI):mass calcd. for C₁₁H₆ClFN₄, 248.03; m/z found, 249.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.22 (s, 1H), 7.67-7.60 (m, 2H), 7.46 (dd, J=8.4, 2.0,1H), 7.37 (s, 2H).

Step B

To a 200 mL round-bottomed flask were added a stirbar,6-amino-3-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile (1.175 g,4.73 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.583 g,6.23 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(194 mg, 0.247 mmol), and KOAc (1.43 g, 14.6 mmol). The flask was fittedwith a septum and sparged with nitrogen for 30 min before adding 48 mLof thoroughly N₂ sparged THF via syringe. The mixture was then heated at80° Celsius for 16.5 hours before cooling the mixture to rt andconcentrating to dryness. The dark residue was taken up in DCM, filteredthrough a plug of celite, and concentrated to dryness. The residue wassubjected to FCC to give the title compound. ¹H NMR (600 MHz, DMSO-d₆) δ8.23 (s, 1H), 7.66-7.58 (m, 2H), 7.53-7.46 (d, J=10.2, 1H), 7.40 (s,2H), 1.34 (s, 12H).

5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amineStep A: 4-Bromo-2-fluorobenzoyl chloride

A solution of 4-bromo-2-fluorobenzoic acid (10.8 g, 50.0 mmol) in SOCl₂(50 mL) was stirred at 70° Celsius for 1 hour. After cooling to rt, theresulting mixture was concentrated to give 4-bromo-2-fluorobenzoylchloride as colorless oil, which was used directly in the next stepwithout purification.

Step B: 2-(4-Bromo-2-fluorobenzoyl)-hydrazinecarbothioamide

Hydrazinecarbothioamide (6.8 g, 75 mmol) was added to a solution of4-bromo-2-fluorobenzoyl chloride (11.8 g, 50.0 mmol) in THF (50 mL) atrt and stirred for 1 hour. The reaction mixture was concentrated to give2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide as a white solid,which was used directly in the next step without purification. MS (ESI):mass calcd. for C₈H₇BFN₃OS, 290.95, m/z found, 292.1 [M+H]⁺.

Step C: 5-(4-Bromo-2-fluorophenyl)-1,3,4-thiadiazol-2-amine

H₂SO₄ (2 mL) was added to a solution of2-(4-bromo-2-fluorobenzoyl)-hydrazinecarbothioamide (2.9 g, 10.0 mmol)in pentanoic acid (5 mL) and the resulting mixture was stirred at 110°Celsius for 2 hours. After cooling to rt, the reaction mixture waspoured into ice-water (20 mL) and treated with NH₃.H₂O (15 mL).5-(4-Bromo-2-fluorophenyl)-1,3,4-thiadiazol-2-amine was then isolatedvia vacuum filtration and air dried. MS (ESI): mass calcd. forC₈H₅BFN₃OS, 272.94, m/z found, 274.1 [M+H]⁺.

Step D

To a solution of 5-(4-bromo-2-fluorophenyl)-1,3,4-thiadiazol-2-amine(2.73 g, 10.0 mmol) in 1,4-dioxane (20 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.54 g,10.0 mmol) and KOAc (1.5 g, 20.0 mmol). The mixture was sparged with N₂for 10 min. Pd(dppf)Cl₂.CH₂Cl₂ (82 mg, 0.1 mmol) was then added, and themixture, stirred at 80° Celsius for 1 hour under N₂. After cooling tort, the reaction mixture was filtered through a pad of anhydrous Na₂SO₄and the filtrate concentrated to dryness. The residue was purified byFCC to give the title compound. MS (ESI): mass calcd. for C₁₄H₁₇N₃BO₂SBr321.11, m/z found 322.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.19 (m,1H), 7.65 (dd, J=7.8, 1.0, 1H), 7.57 (d, J=11.3, 1H), 5.39 (s, 2H), 1.36(s, 12H).

3′-Fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideStep A: 4′-Bromo-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide

1-Bromo-2-fluoro-4-iodobenzene (6.30 g, 20.9 mmol) and(2-(N-methyl-sulfamoyl)-phenyl)boronic acid (4.50 g, 20.9 mmol) wereadded to a 250 mL flask equipped with a stir bar and reflux condenser.1,4-Dioxane (50 mL) and Na₂CO₃ (2 M, 50 mL) were added. Argon wasbubbled through the solvent while it was rapidly stirred for 10 minutesbefore Pd(dppf)Cl₂.CH₂Cl₂ (766 mg, 1.05 mmol) was added and the reactionwas stirred at 80° Celsius for 15 hours. The reaction was then dilutedwith 50 mL of water and extracted with ethyl acetate (1×50 mL, 3×100mL). The combined organic extracts were dried with Na₂CO₃, filtered andconcentrated to dryness. The crude product was purified by FCC to give4′-bromo-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide. ¹H NMR (500MHz, CDCl₃) δ 8.17-8.11 (m, 1H), 7.66-7.59 (m, 2H), 7.59-7.54 (m, 1H),7.33-7.29 (m, 1H), 7.28-7.23 (m, 1H), 7.20-7.13 (m, 1H), 3.67-3.56 (dd,J=10.1, 4.5, 1H), 2.46-2.43 (d, J=5.3, 3H).

Step B:3′-Fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

4′-Bromo-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide (2.0 g, 5.8mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.95g, 11.6 mmol) and anhydrous KOAc (1.71 g, 17.4 mmol) and 1,4-dioxane (50mL) were added to a flask, equipped with a stir bar and refluxcondenser. The reaction mixture was sparged with argon for 10 min,before adding Pd(dppf)Cl₂.CH₂Cl₂ (0.425 g, 0.58 mmol) was added. Theflask was heated at 80° Celsius for 15 hours before cooling to rt,diluting with ethyl acetate (50 mL), filtering through Na₂SO₄ andconcentrating to dryness. The crude product was purified by FCC toprovide the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.12 (dd,J=7.8, 1.4, 1H), 7.87-7.78 (dd, J=7.6, 6.2, 1H), 7.64-7.59 (dd, J=7.5,1.5, 1H), 7.58-7.51 (m, 1H), 7.35-7.27 (m, 2H), 7.19-7.11 (dd, J=9.6,1.5, 1H), 3.57-3.45 (d, J=5.5, 1H), 2.41-2.37 (d, J=5.4, 3H), 1.39 (s,12H).

N-(tert-Butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate D using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acidin Step A. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (dd, J=7.9, 1.4, 1H), 7.81(dd, J=7.6, 6.2, 1H), 7.62-7.53 (m, 1H), 7.53-7.46 (m, 1H), 7.36-7.30(m, 1H), 7.29-7.27 (m, 1H), 7.19 (dd, J=9.9, 1.5, 1H), 3.61 (s, 1H),1.39 (s, 12H), 1.04 (s, 9H).

3′-Fluoro-N-(2-hydroxyethyl)-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate D using 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide inStep A. ¹H NMR (500 MHz, CD₃OD) δ 8.09-8.03 (dd, J=8.0, 1.3, 1H),7.76-7.70 (dd, J=7.6, 6.2, 1H), 7.68-7.62 (m, 1H), 7.61-7.54 (dd, J=8.5,7.1, 1H), 7.37-7.31 (dd, J=7.5, 1.4, 1H), 7.24-7.20 (dd, J=7.6, 1.5,1H), 7.16-7.11 (dd, J=10.0, 1.5, 1H), 3.48-3.43 (t, J=5.9, 2H),2.88-2.82 (t, J=5.9, 2H), 1.37 (s, 12H).

5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indol-7-amine

The title compound was prepared using analogous methods described inIntermediate D using 7-amino-5-bromoindole in Step A. MS (ESI): masscalcd. for C₂₀H₂₂BFN₂O₂, 352.18; m/z found, 353.3 [M+H]⁺.

3-Amino-6-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile

To a solution of 3-amino-6-bromopyrazine-2-carbonitrile (2.00 g, 9.55mmol) in 1,4-dioxane (48 mL), were added(4-chloro-2-fluorophenyl)boronic acid (1.66 g, 9.55 mmol) and aqueousNa₂CO₃ (2 M, 24 mL, 48 mmol) and the reaction mixture sparged with N₂gas for 10 min. Pd(dppf)Cl₂.CH₂Cl₂ (0.349 g, 0.477 mmol) was then addedand the reaction mixture sparged for an additional 10 min with N₂ gas.The reaction vessel was sealed and heated for 3 hours at 80° Celsius.The mixture was cooled to rt, filtered through celite, and the filtercake washed with EtOAc (300 mL). The filtrate was washed with a 1:1mixture of brine/H₂O (2×100 mL). The organic phase was concentrated todryness and subjected to FCC to give the title compound (1.99 g, 84%).MS (ESI): mass calcd. for C₁₁H₆ClFN₄, 248.03; m/z found 249.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.67 (d, J=2.0, 1H), 7.83 (m, 1H), 7.25-7.08 (m,2H), 5.36 (s, 2H).

3-Amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile

To a solution of3-amino-6-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile (0.290 g,1.17 mmol) in 1,4-dioxane (12 mL), were added(4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.370 g,1.46 mmol) and KOAc (0.343 g, 3.50 mmol). The reaction mixture spargedwith N₂ gas for 10 min, before addingchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(18 mg, 0.023 mmol) and then sparged for an additional 10 min with N₂gas. The reaction vessel was sealed, heated 3 hours at 80° Celsius andcooled to rt. The mixture was filtered through celite and the filtercake washed with EtOAc (30 mL). The filtrate was concentrated in vacuoonto silica gel and purified via FCC to give the product which was thentriturated with hexanes to give3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile(0.25 g, 63%). MS (ESI): mass calcd. for C₁₇H₁₈BFN₄O₂, 340.15; m/z found341.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, J=1.8, 1H), 7.94 (m,1H), 7.67 (dd, J=7.7, 1.1, 1H), 7.58 (dd, J=11.8, 1.1, 1H), 5.35 (s,2H), 1.36 (s, 12H).

2-Bromo-N-cyclohexylbenzenesulfonamide

To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride(1.053 g, 4.12 mmol), cyclohexylamine (431 mg, 4.34 mmol) and drypyridine (5 mL). The mixture was stirred for 3 hours before adding it toa separatory funnel containing 1 N HCl and EtOAc. The layers were mixedthoroughly and then separated. The organic layer was then washed withwater followed by sat. NaHCO₃, dried over MgSO₄, filtered and evaporatedto dryness to give the title compound. MS (ESI): mass calcd. forC₁₂H₁₆NO₂SBr 317.01, m/z found 318.0 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ8.14 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.2, 1H), 7.49-7.42 (m, 1H),7.42-7.35 (m, 1H), 5.05 (d, J=7.7, 1H), 3.19-3.04 (m, 1H), 1.79-1.66 (m,2H), 1.66-1.57 (m, 2H), 1.52-1.44 (m, 1H), 1.28-1.04 (m, 5H).

2-Bromo-N-cyclopropylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using cyclopropylamine. ¹H NMR (500 MHz,CDCl₃) δ 8.19 (dd, J=7.8, 1.8, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.51-7.45(m, 1H), 7.44-7.39 (m, 1H), 5.46 (s, 1H), 2.21-2.08 (m, 1H), 0.69-0.60(m, 2H), 0.60-0.51 (m, 2H).

2-Bromo-N-cyclopentylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using cyclopentylamine. ¹H NMR (500 MHz,DMSO-d₆) δ 8.02 (dd, J=7.7, 1.8, 1H), 7.84 (dd, J=7.8, 1.3, 2H),7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 3.51-3.40 (m, 1H), 1.64-1.49 (m,4H), 1.45-1.30 (m, 4H).

2-Bromo-N-(2-methylpropyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using isobutylamine. ¹H NMR (500 MHz, CDCl₃)δ 8.12 (dd, J=7.8, 1.8, 1H), 7.72 (dd, J=7.9, 1.3, 1H), 7.48-7.43 (m,1H), 7.43-7.37 (m, 1H), 5.18-5.03 (m, 1H), 2.67 (t, J=6.6, 2H),1.78-1.64 (m, 1H), 0.87 (d, J=6.7, 6H).

2-Bromo-N-(2-phenylethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using 2-phenethylamine. ¹H NMR (600 MHz,CDCl₃) δ 8.14-8.09 (dd, J=7.9, 1.7, 1H), 7.69-7.63 (dd, J=7.8, 1.2, 1H),7.47-7.42 (m, 1H), 7.42-7.36 (m, 1H), 7.29-7.24 (m, 2H), 7.24-7.17 (m,1H), 7.12-7.06 (m, 2H), 5.16-5.00 (t, J=6.1, 1H), 3.23-3.10 (m, 2H),2.84-2.73 (t, J=7.0, 2H).

2-Bromo-N-(cyclopropylmethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using cyclopropylmethylamine. ¹H NMR (500MHz, CDCl₃) δ 8.18 (dd, J=7.8, 1.7, 1H), 7.70 (dd, J=7.9, 1.2, 1H),7.50-7.43 (m, 1H), 7.42-7.36 (m, 1H), 5.52 (s, 1H), 1.17-1.09 (m, 3H),0.89-0.76 (m, 2H), 0.50-0.41 (m, 2H).

2-Bromo-N-(2,3-dihydro-1H-inden-2-yl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using 2,3-dihydro-1H-inden-2-amine. ¹H NMR(600 MHz, DMSO-d₆) δ 8.34-8.27 (d, J=7.0, 1H), 8.09-8.04 (dd, J=7.7,1.8, 1H), 7.91-7.85 (dd, J=7.8, 1.3, 1H), 7.64-7.54 (m, 2H), 7.17-7.06(m, 4H), 4.01-3.92 (m, 1H), 2.98-2.89 (m, 2H), 2.87-2.79 (m, 2H).

racemic 2-Bromo-N-(2,2,2-trifluoro-1-methylethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using racemic2-amino-1,1,1-trifluoropropane. ¹H NMR (500 MHz, CDCl₃) δ 8.10 (dd,J=7.7, 1.9, 1H), 7.74 (dd, J=7.7, 1.4, 1H), 7.49-7.38 (m, 2H), 5.33 (d,J=9.8, 1H), 4.03-3.88 (m, 1H), 1.29 (d, J=7.0, 3H).

2-Bromo-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (S)-2-amino-1,1,1-trifluoropropane.

racemic (endo)-N-Bicyclo[2.2.1]hept-2-yl-2-bromobenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using racemic(endo)-bicyclo[2.2.1]heptan-2-amine ¹H NMR (500 MHz, CDCl₃) δ 8.13 (dd,J=7.8, 1.8, 1H), 7.71 (dd, J=7.9, 1.3, 1H), 7.49-7.42 (m, 1H), 7.42-7.37(m, 1H), 4.98 (d, J=7.1, 1H), 3.17-3.04 (m, 1H), 2.27-2.14 (m, 1H), 2.05(d, J=3.7, 1H), 1.62-1.50 (m, 1H), 1.45-1.28 (m, 3H), 1.28-1.17 (m, 1H),1.17-1.08 (m, 1H), 1.05-0.91 (m, 2H).

2-Bromo-N-(cyclobutylmethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using cyclobutylmethylamine. ¹H NMR (500MHz, CDCl₃) δ 8.12 (dd, J=7.8, 1.8, 1H), 7.72 (dd, J=7.8, 1.3, 1H),7.49-7.43 (m, 1H), 7.43-7.36 (m, 1H), 5.04 (d, J=6.0, 1H), 2.89 (dd,J=7.4, 6.1, 2H), 2.45-2.31 (m, 1H), 2.04-1.91 (m, 2H), 1.90-1.71 (m,2H), 1.64-1.52 (m, 2H).

2-Bromo-N-(1-methylcyclobutyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using 1-amino-1-methylcyclobutane. ¹H NMR(500 MHz, CDCl₃) δ 8.13 (dd, J=7.8, 1.7, 1H), 7.70 (dd, J=7.9, 1.3, 1H),7.47-7.41 (m, 1H), 7.40-7.34 (m, 1H), 5.26 (s, 1H), 2.26-2.13 (m, 2H),1.86-1.76 (m, 2H), 1.76-1.59 (m, 2H), 1.32 (t, J=0.8, 3H).

2-Bromo-N-(1,1-dimethylpropyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using 2-methylbutan-2-amine. ¹H NMR (500MHz, DMSO-d₆) δ 7.81 (dd, J=7.8, 1.7, 1H), 7.58 (dd, J=7.8, 1.3, 1H),7.35-7.29 (m, 1H), 7.29-7.24 (m, 1H), 1.24 (q, J=7.4, 2H), 0.80 (s, 6H),0.52 (t, J=7.4, 3H).

2-Bromo-N-(2,2,2-trifluoro-1,1-dimethylethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using1,1,1-trifluoro-2-methylpropan-2-amine. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61(s, 1H), 8.05 (dd, J=7.7, 1.8, 1H), 7.86 (dd, J=7.7, 1.4, 1H), 7.62-7.57(m, 1H), 7.57-7.52 (m, 1H), 1.30 (s, 6H).

2-Bromo-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using(R)-2,2,2-trifluoro-1-phenylethanamine. ¹H NMR (600 MHz, DMSO-d₆) δ9.64-9.53 (d, J=10.2, 1H), 8.03-7.91 (dd, J=7.8, 1.7, 1H), 7.68-7.62(dd, J=7.8, 1.2, 1H), 7.53-7.39 (m, 4H), 7.34-7.23 (m, 3H), 5.25-5.11(m, 1H).

2-Bromo-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using(S)-2,2,2-trifluoro-1-phenylethanamine.

2-Bromo-N-[(1R)-1-phenylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (R)-1-phenylethanamine ¹H NMR (600MHz, DMSO-d₆) δ 8.46-8.34 (d, J=8.4, 1H), 7.94-7.83 (dd, J=7.7, 1.9,1H), 7.74-7.65 (dd, J=7.7, 1.4, 1H), 7.50-7.37 (m, 2H), 7.27-7.07 (m,5H), 4.42-4.29 (m, 1H), 1.37-1.27 (d, J=7.0, 3H).

2-Bromo-N-[(1R)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (R)-2,3-dihydro-1H-inden-1-amine. ¹HNMR (600 MHz, DMSO-d₆) δ 8.47-8.39 (d, J=9.0, 1H), 8.14-8.06 (dd, J=7.7,1.8, 1H), 7.93-7.87 (dd, J=7.8, 1.3, 1H), 7.64-7.53 (m, 2H), 7.23-7.10(m, 4H), 4.77-4.64 (m, 1H), 2.91-2.78 (m, 1H), 2.72-2.61 (m, 1H),2.21-2.10 (m, 1H), 1.91-1.77 (m, 1H).

2-Bromo-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (S)-2,3-dihydro-1H-inden-1-amine. NMRspectra as for Intermediate AB.

2-Bromo-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (S)-3-amino-1-ethylazepan-2-one. ¹HNMR (600 MHz, DMSO-d₆) δ 8.04-7.99 (dd, J=7.8, 1.7, 1H), 7.84-7.80 (dd,J=7.9, 1.3, 1H), 7.58-7.53 (m, 2H), 7.53-7.49 (m, 1H), 4.13-4.04 (m,1H), 3.40-3.31 (m, 1H), 3.30-3.15 (m, 3H), 1.85-1.73 (m, 2H), 1.73-1.63(m, 1H), 1.62-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.16 (m, 1H),0.96-0.88 (t, J=7.1, 3H).

2-Bromo-N-[(3S)-2-oxoazepan-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (S)-3-aminoazepan-2-one. ¹H NMR (600MHz, DMSO-d₆) δ 8.05-8.01 (dd, J=7.8, 1.7, 1H), 7.96-7.91 (m, 1H),7.85-7.81 (dd, J=7.8, 1.3, 1H), 7.60-7.55 (m, 1H), 7.55-7.50 (m, 1H),7.47-7.43 (d, J=6.0, 1H), 3.95-3.86 (m, 1H), 3.04-2.93 (m, 2H),1.89-1.79 (m, 2H), 1.71-1.62 (m, 1H), 1.59-1.44 (m, 2H), 1.20-1.07 (m,1H).

2-Bromo-N-[(3S)-1-methyl-2-oxoazepan-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (S)-3-amino-1-methylazepan-2-one. MS(ESI): mass calcd. for C₁₃H₁₇BrN₂O₃S 360.01, m/z found 361.0 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.03-8.00 (dd, J=7.8, 1.8, 1H), 7.84-7.81 (dd,J=7.8, 1.3, 1H), 7.59-7.50 (m, 3H), 4.17-4.07 (m, 1H), 3.48-3.38 (m,1H), 3.20-3.09 (m, 1H), 2.87-2.79 (s, 3H), 1.92-1.81 (dd, J=14.4, 3.4,1H), 1.81-1.70 (m, 1H), 1.67-1.52 (m, 2H), 1.52-1.41 (m, 1H), 1.34-1.21(m, 1H).

2-Bromo-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using1,2,2,6,6-pentamethylpiperidin-4-amine. MS (ESI): mass calcd. forC₁₆H₂₅BrN₂O₂S 388.08, m/z found 389.1 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆)δ 8.07-8.03 (dd, J=7.8, 1.7, 1H), 7.87-7.81 (m, 2H), 7.61-7.56 (m, 1H),7.56-7.51 (m, 1H), 3.32-3.21 (m, 1H), 2.11-2.02 (s, 3H), 1.46-1.37 (m,2H), 1.35-1.26 (m, 2H), 1.01-0.92 (s, 6H), 0.83-0.74 (s, 6H).

2-Bromo-N-phenylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using aniline. ¹H NMR (600 MHz, DMSO-d₆) δ10.68-10.56 (s, 1H), 8.13-8.02 (dd, J=7.9, 1.7, 1H), 7.85-7.75 (dd,J=7.8, 1.3, 1H), 7.62-7.46 (m, 2H), 7.25-7.16 (m, 2H), 7.12-7.04 (m,2H), 7.02-6.93 (m, 1H).

2-Bromo-N-pyridin-3-ylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using 3-aminopyridine. MS (ESI): mass calcd.for C₁₁H₉BrN₂O₂S 311.96, m/z found 312.9 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) δ 11.05-10.87 (s, 1H), 8.40-8.29 (m, 1H), 8.25-8.17 (dd, J=4.7,1.4, 1H), 8.15-8.06 (dd, J=7.8, 1.8, 1H), 7.93-7.78 (dd, J=7.8, 1.3,1H), 7.66-7.52 (m, 2H), 7.47-7.44 (dd, J=2.7, 1.4, 1H), 7.32-7.23 (m,2H).

2-Bromo-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate K using (R)-2-aminopropan-1-ol. MS (ESI): masscalcd. for C₉H₁₂NOSBr 292.97, m/z found 294.0 [M+H]⁺; ¹H NMR (600 MHz,CDCl₃) δ 8.13 (dd, J=7.8, 1.8, 1H), 7.72 (dd, J=7.9, 1.3, 1H), 7.48-7.43(m, 1H), 7.43-7.37 (m, 1H), 5.42 (d, J=7.4, 1H), 3.60-3.50 (m, 1H),3.49-3.40 (m, 1H), 3.38-3.28 (m, 1H), 2.16 (t, J=5.4, 1H), 1.04 (d,J=6.8, 3H).

2-Bromo-N-ethylbenzenesulfonamide

To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride(0.995 g, 3.89 mmol), and THF (5 mL). The vial was then charged withEtNH₂ in THF (5 mL, 2.0 M). The mixture was stirred for 24 hours beforeadding it to a separatory funnel containing 1 N HCl and EtOAc. Thelayers were mixed thoroughly and then separated. The organic layer wasthen washed with water followed by sat. NaHCO₃, dried over MgSO₄,filtered and concentrated to dryness to give the crude product.Subjecting the oil to FCC yielded the title compound (580 mg, 56%). ¹HNMR (600 MHz, CDCl₃) δ 8.17-8.10 (dd, J=7.8, 1.7, 1H), 7.75-7.69 (dd,J=7.8, 1.2, 1H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.16-4.91 (t,J=6.7, 1H), 3.06-2.87 (m, 2H), 1.19-1.00 (t, J=7.3, 3H).

2-Bromo-N-methylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AK using 0.5 M methylamine in 1,4-dioxane. ¹HNMR (600 MHz, CDCl₃) δ 8.15-8.11 (dd, J=7.8, 1.7, 1H), 7.75-7.70 (dd,J=7.8, 1.3, 1H), 7.49-7.45 (m, 1H), 7.44-7.39 (m, 1H), 5.11-5.00 (d,J=6.6, 1H), 2.66-2.55 (d, J=5.4, 3H).

2-Bromo-N-[(1S)-2-hydroxy-1-methylethyl]benzenesulfonamide

To a 500 mL round-bottomed flask were added a stirbar,(S)-2-aminopropan-1-ol (2.151 g, 28.65 mmol), dry DCM (100 mL), andDIPEA (14.0 mL, 81.2 mmol). The mixture was then treated with2-bromobenzene-1-sulfonyl chloride (6.981 g, 27.32 mmol) and stirred for66.5 hours before concentrating to dryness and subjecting the residue toFCC to give the title compound. (7.31 g, 91%).

2-Bromo-N-(2-hydroxy-1,1-dimethylethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using 2-amino-2-methylpropan-1-ol. MS(ESI): mass calcd. for C₁₀H₁₄BrNO₃S 306.99, m/z found 330.0 [M+Na]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.14 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.9, 1.2,1H), 7.50-7.42 (m, 1H), 7.42-7.35 (m, 1H), 5.33 (s, 1H), 3.46 (d, J=6.3,2H), 1.11 (s, 6H).

2-Bromo-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using (R)-2-amino-3-methylbutan-1-ol. MS(ESI): mass calcd. for C₁₁H₁₆BrNO₃S 321.00, m/z found 322.0 [M+H]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.15-8.06 (m, 1H), 7.78-7.67 (m, 1H), 7.50-7.42(m, 1H), 7.42-7.34 (m, 1H), 5.39 (s, 1H), 3.65-3.54 (m, 1H), 3.54-3.43(m, 1H), 3.11-3.01 (m, 1H), 1.82 (d, J=5.7, 1H), 0.95-0.83 (m, 3H),0.83-0.73 (m, 3H).

2-Bromo-N-[(3S)-2-oxopiperidin-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using (S)-3-aminopiperidin-2-one. MS (ESI):mass calcd. for C₁₁H₁₃BrN₂O₃S 331.98, m/z found 333.0 [M+H]⁺; ¹H NMR(600 MHz, CDCl₃) δ 8.08 (dd, J=7.8, 1.8, 1H), 7.71 (dd, J=7.8, 1.3, 1H),7.46-7.40 (m, 1H), 7.40-7.36 (m, 1H), 6.77 (s, 1H), 6.52-6.41 (m, 1H),3.61-3.49 (m, 1H), 3.34-3.18 (m, 2H), 2.43-2.32 (m, 1H), 1.96-1.84 (m,1H), 1.81-1.69 (m, 2H).

2-Bromo-N-(trans-4-hydroxycyclohexyl)benzenesulfonamide

To a 20 mL vial were added a stir-bar, trans-4-aminocyclohexanol (683mg, 4.50 mmol), DMF (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture wasthen treated with 2-bromobenzene-1-sulfonyl chloride (1.00 g, 3.93 mmol)and the mixture stirred for 2 hours before subjecting the vial's contentto FCC to give the title compound. (978 mg, 74%). MS (ESI): mass calcd.for C₁₂H₁₆BrNO₃S 333.00, m/z found 334.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.12 (dd, J=7.8, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.49-7.43 (m,1H), 7.43-7.37 (m, 1H), 5.10 (d, J=7.5, 1H), 3.62-3.47 (m, 1H),3.11-3.01 (m, 1H), 2.12 (s, 1H), 1.91-1.75 (m, 4H), 1.31-1.15 (m, 4H).

{(3S)-1-[(2-Bromophenyl)sulfonyl]pyrrolidin-3-yl}methanol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AQ using (S)-pyrrolidin-3-ylmethanol. ¹H NMR(600 MHz, CDCl₃) δ 8.06 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.9, 1.2, 1H),7.44-7.38 (m, 1H), 7.38-7.32 (m, 1H), 3.61-3.54 (m, 1H), 3.54-3.45 (m,3H), 3.39-3.33 (m, 1H), 3.17 (dd, J=9.8, 6.4, 1H), 2.53-2.39 (m, 2H),2.04-1.94 (m, 1H), 1.74-1.65 (m, 1H).

{(3R)-1-[(2-Bromophenyl)sulfonyl]pyrrolidin-3-yl}methanol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AQ using (R)-pyrrolidin-3-ylmethanol.

2-Bromo-N-[(3R)-2-oxopiperidin-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AQ using (R)-3-aminopiperidin-2-one.

2-Bromo-N-(3-hydroxy-1,1-dimethylpropyl)benzenesulfonamide

To a 20 mL vial were added a stirbar, 3-amino-3-methylbutan-1-ol (428mg, 4.15 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture wasthen treated with 2-bromobenzene-1-sulfonyl chloride (994 mg, 3.89 mmol)and stirred for 12.5 hours before concentrating to dryness andsubjecting the residue to FCC to give the title compound. (676 mg, 54%).MS (ESI): mass calcd. for C₁₁H₁₆BrNO₃S 321.00, m/z found 344.0 [M+Na]⁺;¹H NMR (600 MHz, CDCl₃) δ 8.15 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.8,1.2, 1H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 1H), 6.15 (s, 1H), 3.93-3.81(m, 2H), 1.76 (t, J=6.0, 2H), 1.20 (s, 6H).

tert-Butyl(3S)-3-{[(2-bromophenyl)sulfonyl](methyl)amino}piperidine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl3-(methylamino)piperidine-1-carboxylate. MS (ESI): mass calcd. forC₁₇H₂₅BrN₂O₄S 432.07, m/z found 455.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.14 (dd, J=7.9, 1.7, 1H), 7.72 (dd, J=7.9, 1.3, 1H), 7.46-7.40 (m, 1H),7.40-7.35 (m, 1H), 4.06 (s, 2H), 3.67 (s, 1H), 2.85 (s, 3H), 2.72 (s,1H), 2.47 (s, 1H), 1.86 (d, J=11.8, 1H), 1.75-1.65 (m, 1H), 1.65-1.55(m, 1H), 1.54-1.46 (m, 1H), 1.38 (s, 9H).

tert-Butyl(3R)-3-{[(2-bromophenyl)sulfonyl](methyl)amino}piperidine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl3-(methylamino)piperidine-1-carboxylate.

2-Bromo-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol. MS (ESI): mass calcd. forC₁₅H₁₄BrNO₃S 366.99, m/z found 389.9 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.20 (dd, J=7.7, 1.9, 1H), 7.79 (dd, J=7.8, 1.4, 1H), 7.50-7.42 (m, 2H),7.24-7.16 (m, 4H), 5.85 (d, J=8.2, 1H), 4.70-4.63 (m, 1H), 4.38-4.31 (m,1H), 3.09-2.97 (m, 1H), 2.95-2.86 (m, 1H), 2.12 (d, J=5.2, 1H).

2-Bromo-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1S,2R)-2-amino-1-phenylpropane-1,3-diol. MS (ESI): mass calcd. forC₁₅H₁₆BrNO₄S 384.00, m/z found 407.9 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ7.88 (dd, J=7.6, 1.9, 1H), 7.54 (dd, J=7.6, 1.5, 1H), 7.34-7.26 (m, 2H),7.23-7.19 (m, 2H), 7.17-7.09 (m, 3H), 5.89 (d, J=6.4, 1H), 4.97 (dd,J=4.3, 2.4, 1H), 3.83-3.73 (m, 1H), 3.73-3.64 (m, 1H), 3.48-3.38 (m,1H), 3.05 (d, J=2.6, 1H), 2.37-2.27 (m, 1H).

N-[(1S)-1-Benzyl-2-hydroxyethyl]-2-bromobenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-amino-3-phenylpropan-1-ol. MS(ESI): mass calcd. for C₁₅H₁₆BrNO₃S 369.00, m/z found 392.0 [M+Na]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.07 (dd, J=7.8, 1.7, 1H), 7.62 (dd, J=7.9, 1.2,1H), 7.45-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.20-7.10 (m, 3H), 7.05-6.95(m, 2H), 5.46 (d, J=6.8, 1H), 3.63-3.54 (m, 1H), 3.54-3.43 (m, 2H),2.88-2.78 (m, 1H), 2.78-2.68 (m, 1H), 2.14-1.97 (m, 1H).

2-Bromo-N-[(2R)-2-hydroxy-2-phenylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-2-amino-3-phenylpropan-1-ol. ¹HNMR (600 MHz, CDCl₃) δ 8.10 (dd, J=7.8, 1.8, 1H), 7.71 (dd, J=7.8, 1.3,1H), 7.47-7.42 (m, 1H), 7.42-7.37 (m, 1H), 7.33-7.28 (m, 2H), 7.28-7.25(m, 3H), 5.68-5.57 (m, 1H), 4.78 (dd, J=8.7, 3.7, 1H), 3.26-3.15 (m,1H), 3.04-2.94 (m, 1H), 2.41 (s, 1H).

2-Bromo-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1S,2S)-2-(methylamino)-1-phenylpropan-1-ol. MS (ESI): mass calcd. forC₁₆H₁₈BrNO₃S 383.02, m/z found 406.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.19 (dd, J=7.9, 1.7, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.49-7.44 (m, 1H),7.41-7.36 (m, 1H), 7.34-7.29 (m, 2H), 7.29-7.25 (m, 3H), 4.45 (dd,J=9.4, 3.4, 1H), 3.95-3.85 (m, 1H), 3.05 (d, J=3.4, 1H), 2.98 (s, 3H),0.97-0.86 (d, J=6.7, 3H).

2-Bromo-N-[(2R)-2,3-dihydroxypropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-1-aminoethane-1,2-diol. MS (ESI):mass calcd. for C₉H₁₂BrNO₄S 308.97, m/z found 310.0 [M+H]⁺; ¹H NMR (600MHz, CDCl₃) δ 8.05 (dd, J=7.8, 1.7, 1H), 7.68 (dd, J=7.9, 1.3, 1H),7.49-7.40 (m, 1H), 7.40-7.32 (m, 1H), 6.18 (t, J=6.3, 1H), 3.95-3.75 (m,3H), 3.64 (dd, J=11.8, 3.6, 1H), 3.54 (dd, J=11.6, 6.0, 1H), 3.06-2.97(m, 1H), 2.97-2.85 (m, 1H).

2-Bromo-N-[(3S)-2-oxopyrrolidin-3-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-3-aminopyrrolidin-2-one. MS(ESI): mass calcd. for C₁₀H₁₁BrN₂O₃S 317.97, m/z found 318.9 [M+H]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.14-8.05 (m, 1H), 7.71 (dd, J=7.8, 1.3, 1H),7.49-7.36 (m, 2H), 7.06 (s, 1H), 6.22 (d, J=4.7, 1H), 3.81-3.68 (m, 1H),3.41-3.29 (m, 1H), 3.29-3.18 (m, 1H), 2.47-2.34 (m, 1H), 2.12-2.00 (m,1H).

2-Bromo-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 1-amino-2-methylpropan-2-ol. MS(ESI): mass calcd. for C₁₀H₁₄BrNO₃S 306.99, m/z found 290.0 [M-OH]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.11 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.8, 1.3,1H), 7.48-7.43 (m, 1H), 7.43-7.38 (m, 1H), 5.53 (t, J=6.0, 1H), 2.79 (d,J=6.6, 2H), 1.22 (s, 6H).

2-Bromo-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-2-amino-1,1,1-trifluoropropane.

tert-Butyl({(2R)-1-[(2-bromophenyl)sulfonyl]pyrrolidin-2-yl}methyl)carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-tert-butyl(pyrrolidin-2-ylmethyl)carbamate. MS (ESI): mass calcd. forC₁₆H₂₃BrN₂O₄S 418.06, m/z found 319.0 [M-Boc+H]⁺; ¹H NMR (600 MHz,CDCl₃) δ 8.10 (dd, J=7.9, 1.7, 1H), 7.73 (dd, J=7.9, 1.3, 1H), 7.46-7.41(m, 1H), 7.41-7.36 (m, 1H), 4.99 (t, J=6.5, 1H), 4.05-3.95 (m, 1H),3.50-3.40 (m, 1H), 3.40-3.34 (m, 1H), 3.32-3.17 (m, 2H), 1.98-1.86 (m,2H), 1.86-1.71 (m, 2H), 1.40 (s, 9H).

tert-Butyl 4-{[(2-bromophenyl)sulfonyl]amino}piperidine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl4-aminopiperidine-1-carboxylate. MS (ESI): mass calcd. for C₁₆H₂₃BrN₂O₄S418.06, m/z found 441.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ 8.13 (dd,J=7.8, 1.7, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.49-7.43 (m, 1H), 7.43-7.38(m, 1H), 5.15 (d, J=7.5, 1H), 3.86 (s, 2H), 3.32-3.20 (m, 1H), 2.75 (s,2H), 1.69 (d, J=12.2, 2H), 1.40 (s, 9H), 1.38-1.29 (m, 2H).

1-[(2-Bromophenyl)sulfonyl]azetidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using azetidin-3-ol. MS (ESI): mass calcd.for C₉H₁₀BrNO₃S 290.96, m/z found 292.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.02 (dd, J=7.8, 1.8, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.44-7.40 (m,1H), 7.40-7.35 (m, 1H), 4.61-4.51 (m, 1H), 4.18-4.10 (m, 2H), 3.97-3.91(m, 2H), 2.92 (d, J=6.3, 1H).

racemic 2-Bromo-N-[(1,2-trans)-2-hydroxycyclohexyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingracemic-(1,2-trans)-1R-2-aminocyclohexanol. MS (ESI): mass calcd. forC₁₂H₁₆BrNO₃S 333.00, m/z found 334.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.15 (dd, J=7.8, 1.7, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.50-7.44 (m, 1H),7.44-7.39 (m, 1H), 5.29 (d, J=7.4, 1H), 3.38-3.28 (m, 1H), 2.88-2.77 (m,1H), 2.58 (d, J=3.0, 1H), 2.04-1.96 (m, 1H), 1.77-1.69 (m, 1H),1.59-1.51 (m, 1H), 1.27-1.12 (m, 3H), 1.12-1.01 (m, 1H).

racemic2-Bromo-N-[(1,2-trans)-2-(hydroxymethyl)cyclohexyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingracemic-(1,2-trans)-1R-2-aminocyclohexyl)methanol. MS (ESI): mass calcd.for C₁₃H₁₈BrNO₃S 347.02, m/z found 348.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.13 (dd, J=7.8, 1.7, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.49-7.44 (m,1H), 7.44-7.38 (m, 1H), 5.19-5.06 (m, 1H), 4.10-4.00 (m, 1H), 3.51-3.41(m, 1H), 3.08-2.97 (m, 1H), 2.45-2.36 (m, 1H), 1.72-1.66 (m, 1H),1.66-1.60 (m, 1H), 1.59-1.53 (m, 1H), 1.52-1.46 (m, 1H), 1.41-1.32 (m,1H), 1.31-1.24 (m, 1H), 1.20-1.07 (m, 2H), 1.05-0.96 (m, 1H).

racemic 2-Bromo-N-[(1,2-cis)-2-hydroxycyclohexyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingracemic-(1,2-cis)-1R-2-aminocyclohexanol. MS (ESI): mass calcd. forC₁₂H₁₆BrNO₃S 333.00, m/z found 334.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.13 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.47-7.42 (m, 1H),7.42-7.38 (m, 1H), 5.52 (d, J=7.7, 1H), 3.80-3.72 (m, 1H), 3.27-3.15 (m,1H), 1.80 (d, J=4.8, 1H), 1.74-1.63 (m, 1H), 1.63-1.51 (m, 2H),1.51-1.43 (m, 2H), 1.43-1.36 (m, 1H), 1.36-1.26 (m, 1H), 1.26-1.11 (m,1H).

racemic2-Bromo-N-[(1,2-cis)-2-(hydroxymethyl)cyclohexyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingracemic-(1,2-cis)-1R-2-aminocyclohexyl)methanol. MS (ESI): mass calcd.for C₁₃H₁₈BrNO₃S 347.02, m/z found 348.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.13 (dd, J=7.8, 1.8, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.49-7.44 (m,1H), 7.44-7.39 (m, 1H), 5.43 (d, J=9.3, 1H), 3.76-3.65 (m, 1H),3.65-3.54 (m, 1H), 3.45-3.33 (m, 1H), 2.82 (dd, J=8.9, 5.2, 1H),1.73-1.60 (m, 2H), 1.58-1.51 (m, 1H), 1.42-1.35 (m, 1H), 1.35-1.16 (m,4H), 1.10-0.97 (m, 1H).

5-[(2-Bromophenyl)sulfonyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. MS (ESI): mass calcd. forC₁₂H₁₂BrN₃O₂S 340.98, m/z found 341.9 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.15 (dd, J=7.8, 1.7, 1H), 7.71 (dd, J=7.9, 1.2, 1H), 7.47-7.42 (m, 1H),7.41-7.36 (m, 1H), 7.33 (s, 1H), 4.45 (s, 2H), 3.66 (t, J=5.8, 2H), 2.83(t, J=5.8, 2H).

tert-Butyl ({1-[(2-bromophenyl)sulfonyl]azetidin-3-yl}methyl)carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl(azetidin-3-ylmethyl)carbamate. MS (ESI): mass calcd. for C₁₅H₂₁BrN₂O₄S404.04, m/z found 349.0 [M-tBu+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ 8.04 (dd,J=7.8, 1.8, 1H), 7.73 (dd, J=7.7, 1.3, 1H), 7.44-7.40 (m, 1H), 7.40-7.35(m, 1H), 4.71 (s, 1H), 4.13-4.03 (m, 2H), 3.70 (dd, J=7.9, 5.4, 2H),3.35-3.22 (m, 2H), 2.78-2.64 (m, 1H), 1.40 (s, 9H).

tert-Butyl3-({[(2-bromophenyl)sulfonyl]amino}methyl)azetidine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl3-(aminomethyl)azetidine-1-carboxylate. ¹H NMR (600 MHz, CDCl₃) δ 8.12(dd, J=7.8, 1.7, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.50-7.45 (m, 1H),7.45-7.39 (m, 1H), 5.42-5.30 (m, 1H), 3.96-3.85 (m, 2H), 3.52 (d, J=9.3,2H), 3.17-3.02 (m, 2H), 2.69-2.54 (m, 1H), 1.39 (s, 9H).

tert-Butyl{(3R)-1-[(2-bromophenyl)sulfonyl]pyrrolidin-3-yl}methylcarbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-tert-butylmethyl(pyrrolidin-3-yl)carbamate. MS (ESI): mass calcd. forC₁₆H₂₃BrN₂O₄S 418.06, m/z found 441.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.08 (dd, J=7.9, 1.8, 1H), 7.73 (dd, J=7.8, 1.3, 1H), 7.46-7.40 (m, 1H),7.40-7.34 (m, 1H), 4.80 (s, 1H), 3.61 (s, 1H), 3.51 (s, 1H), 3.38-3.30(m, 1H), 3.19 (dd, J=9.9, 7.4, 1H), 2.73 (s, 3H), 2.12-2.03 (m, 1H),2.03-1.93 (m, 1H), 1.41 (s, 9H).

tert-Butyl(1R,4R)-5-[(2-bromophenyl)sulfonyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. MS (ESI): mass calcd. forC₁₆H₂₁BrN₂O₄S 416.04, m/z found 439.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.10 (dd, J=7.9, 1.8, 1H), 7.73 (dd, J=8.0, 1.2, 1H), 7.46-7.40 (m, 1H),7.40-7.34 (m, 1H), 4.63-4.39 (m, 2H), 3.59-3.39 (m, 2H), 3.33-3.22 (m,2H), 1.88-1.76 (m, 2H), 1.42 (d, J=5.0, 9H).

tert-Butyl(1S,4S)-5-[(2-bromophenyl)sulfonyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.

4-{1-[(2-Bromophenyl)sulfonyl]piperidin-4-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using4-(piperidin-4-yl)-1H-1,2,4-triazol-5(4H)-one. MS (ESI): mass calcd. forC₁₃H₁₅BrN₄O₃S 386.00, m/z found 387.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ9.63 (s, 1H), 8.10 (dd, J=7.8, 1.8, 1H), 7.75 (dd, J=7.9, 1.3, 1H),7.49-7.43 (m, 1H), 7.43-7.37 (m, 2H), 4.05-3.97 (m, 3H), 2.97-2.89 (m,2H), 2.09-2.03 (m, 2H), 1.89-1.79 (m, 2H).

2-Bromo-N-[(2S)-2,3-dihydroxypropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-3-aminopropane-1,2-diol.

tert-Butyl (cis-4-{[(2-bromophenyl)sulfonyl]amino}cyclohexyl)carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl((cis)-4-aminocyclohexyl)carbamate. MS (ESI): mass calcd. forC₁₇H₂₅BrN₂O₄S 432.07, m/z found 455.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.13 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.8, 1.2, 1H), 7.48-7.43 (m, 1H),7.43-7.38 (m, 1H), 5.17 (s, 1H), 4.45 (s, 1H), 3.47 (s, 1H), 3.30-3.20(m, 1H), 1.66 (s, 2H), 1.60-1.49 (m, 4H), 1.45 (d, J=7.3, 1H), 1.41 (s,9H).

2-Bromo-N-(5-hydroxypentyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 5-aminopentan-1-ol. MS (ESI): masscalcd. for C₁₁H₁₆BrNO₃S 321.00, m/z found 322.0 [M+H]⁺; ¹H NMR (600 MHz,CDCl₃) δ 8.10 (dd, J=7.8, 1.7, 1H), 7.71 (dd, J=7.9, 1.3, 1H), 7.48-7.42(m, 1H), 7.42-7.35 (m, 1H), 5.23 (t, J=6.3, 1H), 3.62-3.50 (m, 2H),2.93-2.83 (m, 2H), 1.55 (s, 1H), 1.52-1.42 (m, 4H), 1.39-1.29 (m, 2H).

2-Bromo-N-(5-hydroxyhexyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 6-aminohexan-1-ol. MS (ESI): masscalcd. for C₁₂H₁₈BrNO₃S 335.02, m/z found 336.0 [M+H]⁺; ¹H NMR (600 MHz,CDCl₃) δ 8.11 (dd, J=7.8, 1.8, 1H), 7.71 (dd, J=7.9, 1.3, 1H), 7.48-7.42(m, 1H), 7.42-7.36 (m, 1H), 5.15 (t, J=6.2, 1H), 3.57 (t, J=6.6, 2H),2.94-2.81 (m, 2H), 1.56-1.35 (m, 5H), 1.33-1.21 (m, 4H).

{(2S)-1-[(2-Bromophenyl)sulfonyl]-2,3-dihydro-1H-indol-2-yl}methanol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-indolin-2-ylmethanol. MS (ESI):mass calcd. for C₁₅H₁₄BrNO₃S 366.99, m/z found 389.9 [M+Na]⁺; ¹H NMR(600 MHz, CDCl₃) δ 8.12 (dd, J=7.9, 1.7, 1H), 7.65 (dd, J=7.9, 1.3, 1H),7.42-7.36 (m, 1H), 7.36-7.31 (m, 1H), 7.27 (d, J=8.1, 1H), 7.14-7.09 (m,1H), 7.09-7.04 (m, 1H), 6.98-6.93 (m, 1H), 4.86-4.78 (m, 1H), 3.81-3.68(m, 2H), 3.28 (dd, J=16.2, 9.6, 1H), 2.88-2.79 (m, 1H), 2.20 (s, 1H).

2-Bromo-N-cyclohexyl-N-(2-hydroxyethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-(cyclohexylamino)ethanol. MS (ESI):mass calcd. for C₁₄H₂₀BrNO₃S 361.03, m/z found 362.0 [M+H]⁺; ¹H NMR (600MHz, CDCl₃) δ 8.14 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.8, 1.3, 1H),7.46-7.40 (m, 1H), 7.40-7.34 (m, 1H), 3.71 (m, 2H), 3.65-3.57 (m, 1H),3.47 (t, J=6.1, 2H), 2.22 (t, J=5.9, 1H), 1.80-1.67 (m, 4H), 1.62-1.53(m, 1H), 1.44-1.32 (m, 2H), 1.27-1.15 (m, 2H), 1.07-0.94 (m, 1H).

(racemic) 1-[(2-Bromophenyl)sulfonyl]azetidine-2-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using racemic-azetidine-2-carboxamide. MS(ESI): mass calcd. for C₁₀H₁₁BrN₂O₃S 319.97, m/z found 319.0 [M+H]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.11-8.07 (m, 1H), 7.83-7.79 (m, 1H), 7.53-7.46(m, 2H), 6.91 (s, 1H), 5.53 (s, 1H), 4.75 (t, J=8.8, 1H), 4.02-3.94 (m,1H), 3.75-3.67 (m, 1H), 2.49-2.39 (m, 2H).

1-[(2-Bromophenyl)sulfonyl]-4-(1H-imidazol-4-yl)piperidine Step A:1-[(2-Bromophenyl)sulfonyl]-4-{1-[(2-bromophenyl)sulfonyl]-1H-imidazol-4-yl}piperidine

To a 20 mL vial were added a stirbar, 4-(1H-imidazol-4-yl)piperidine.HCl(696 mg, 3.71 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). Themixture was then treated with 2-bromobenzene-1-sulfonyl chloride (900mg, 3.52 mmol) and the mixture was stirred for 15.5 hours beforeconcentrating to dryness and subjecting the residue to FCC to give thetitle compound (950 mg, 92%). MS (ESI): mass calcd. for C₂₀H₁₉Br₂N₃O₄S₂586.92 m/z found 587.9 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ 8.20 (dd,J=7.9, 1.8, 1H), 8.08 (dd, J=7.8, 1.7, 1H), 8.06 (d, J=1.3, 1H), 7.75(dd, J=7.7, 1.3, 1H), 7.72 (dd, J=7.9, 1.2, 1H), 7.58-7.53 (m, 1H),7.53-7.49 (m, 1H), 7.45-7.40 (m, 1H), 7.39-7.34 (m, 1H), 6.93-6.91 (m,1H), 3.90-3.82 (m, 2H), 2.93-2.83 (m, 2H), 2.68-2.59 (m, 1H), 2.02 (dd,J=13.9, 3.0, 2H), 1.70-1.59 (m, 2H).

Step B

To a 20 mL vial containing1-[(2-bromophenyl)sulfonyl]-4-{1-[(2-bromophenyl)-sulfonyl]-1H-imidazol-4-yl}piperidine(884 mg, 1.50 mmol) were added a stirbar and DMSO (10 mL). Once the DMSOsolution was homogeneous, LiOH (3 mL, 1.0 M) was added slowly. After 30min the reaction mixture was diluted with EtOAc, washed with water (×4)and brine (×1), dried over MgSO₄, filtered and concentrated to drynessto give the title compound (522 mg, 94%). MS (ESI): mass calcd. forC₁₄H₁₆BrN₃O₂S 369.01 m/z found 370.0 [M+H]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.08 (dd, J=7.9, 1.7, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.62 (s, 1H),7.45-7.41 (m, 1H), 7.40-7.35 (m, 1H), 6.76 (s, 1H), 3.88 (d, J=12.8,1H), 2.90 (m, 2H), 2.76-2.69 (m, 1H), 2.09-2.01 (m, 2H), 1.77-1.67 (m,2H).

tert-Butyl {(3S)-1-[(2-bromophenyl)sulfonyl]piperidin-3-yl}carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butylpiperidin-3-ylcarbamate. MS (ESI): mass calcd. for C₁₆H₂₃BrN₂O₄S 418.06m/z found 441.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ 8.10-8.06 (m, 1H),7.73 (dd, J=7.7, 1.3, 1H), 7.46-7.40 (m, 1H), 7.40-7.35 (m, 1H), 4.88(d, J=8.5, 1H), 3.77 (s, 1H), 3.44 (s, 1H), 3.28 (d, J=11.8, 1H),3.23-3.03 (m, 2H), 1.85-1.55 (m, 4H), 1.39 (s, 9H).

2-Bromo-N,N-bis(2-hydroxyethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2,2′-azanediyldiethanol. MS (ESI):mass calcd. for C₁₀H₁₄BrNO₄S 322.98 m/z found 324.0 [M+H]⁺; ¹H NMR (600MHz, CDCl₃) δ 8.10-8.05 (m, 1H), 7.74 (dd, J=7.8, 1.3, 1H), 7.47-7.42(m, 1H), 7.42-7.37 (m, 1H), 3.83 (dd, J=7.3, 3.8, 4H), 3.48 (t, J=5.0,4H), 3.38 (s, 2H).

tert-Butyl(3S)-4-[(2-bromophenyl)sulfonyl]-3-methylpiperazine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl3-methylpiperazine-1-carboxylate. MS (ESI): mass calcd. forC₁₆H₂₃BrN₂O₄S 418.06 m/z found 319.0 [M-Boc+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.14 (dd, J=7.8, 1.8, 1H), 7.72 (dd, J=7.8, 1.3, 1H), 7.45-7.40 (m,1H), 7.40-7.35 (m, 1H), 4.16-3.73 (m, 3H), 3.63-3.42 (m, 1H), 3.32-3.22(m, 1H), 3.17-2.68 (m, 2H), 1.42 (s, 9H), 1.25-1.09 (m, 3H).

tert-Butyl(3R)-4-[(2-bromophenyl)sulfonyl]-3-methylpiperazine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-tert-butyl3-methylpiperazine-1-carboxylate.

2-Bromo-N-(2-hydroxyethyl)-N-(1-methylethyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-(isopropylamino)ethanol. MS (ESI):mass calcd. for C₁₁H₁₆BrNO₃S 321.00 m/z found 322.0 [M+H]⁺; ¹H NMR (600MHz, CDCl₃) δ 8.15 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.3, 1H),7.46-7.41 (m, 1H), 7.39-7.34 (m, 1H), 4.01 (hept, J=6.7, 1H), 3.74 (m,2H), 3.47 (t, J=6.1, 2H), 2.27 (t, J=5.8, 1H), 1.13 (d, J=6.8, 6H).

tert-Butyl(3R)-4-[(2-bromophenyl)sulfonyl]-3-(hydroxymethyl)piperazine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate. MS (ESI): mass calcd. forC₁₆H₂₃BrN₂O₅S 434.05 m/z found 335.0 [M-Boc+H]⁺; ¹H NMR (600 MHz, CDCl₃)δ 8.16 (dd, J=7.8, 1.8, 1H), 7.73 (dd, J=7.9, 1.3, 1H), 7.47-7.42 (m,1H), 7.42-7.37 (m, 1H), 4.32-3.43 (m, 6H), 3.27-3.15 (m, 1H), 3.15-2.66(m, 3H), 1.44 (s, 9H).

2-Bromo-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-amino-2-methylpropane-1,3-diol. ¹HNMR (600 MHz, CDCl₃) δ 8.14 (dd, J=7.8, 1.7, 1H), 7.73 (dd, J=7.9, 1.3,1H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.93 (s, 1H), 3.72-3.56 (m,4H), 2.53-2.44 (m, 2H), 0.93 (s, 3H).

endo-3-[(2-Bromophenyl)sulfonyl]-3-azabicyclo[3.1.0]hexan-6-amine

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingendo-3-azabicyclo[3.1.0]hexan-6-amine. MS (ESI): mass calcd. forC₁₁H₁₃BrN₂O₂S 315.99 m/z found 317.0 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ7.97 (dd, J=7.7, 1.9, 1H), 7.88 (dd, J=7.7, 1.4, 1H), 7.62-7.58 (m, 1H),7.58-7.54 (m, 1H), 3.42-3.38 (m, 2H), 3.37-3.29 (m, 4H), 2.02 (t, J=2.2,1H), 1.46-1.41 (m, 2H).

tert-Butyl (2-{[(2-bromophenyl)sulfonyl]amino}ethyl)carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using tert-butyl (2-aminoethyl)carbamate.¹H NMR (600 MHz, CDCl₃) δ 8.10 (dd, J=7.7, 1.7, 1H), 7.71 (dd, J=7.9,1.3, 1H), 7.47-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.66 (t, J=5.8, 1H),4.86 (s, 1H), 3.21 (t, J=5.8, 2H), 3.03-2.95 (m, 2H), 1.40 (s, 9H).

2-Bromo-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-amino-3-methylbutan-1-ol. ¹HNMR (600 MHz, CDCl₃) δ 8.11 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.9, 1.2,1H), 7.47-7.42 (m, 1H), 7.41-7.36 (m, 1H), 5.35 (d, J=8.6, 1H),3.63-3.54 (m, 1H), 3.54-3.43 (m, 1H), 3.11-3.01 (m, 1H), 1.88-1.75 (m,2H), 0.86 (d, J=6.9, 3H), 0.80 (d, J=6.8, 3H).

2-Bromo-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-amino-3,3-dimethylbutan-1-ol.MS (ESI): mass calcd. for C₁₂H₁₈BrNO₃S 335.02 m/z found 336.0 [M+H]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.09 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.3,1H), 7.46-7.41 (m, 1H), 7.40-7.35 (m, 1H), 5.40 (d, J=9.4, 1H),3.66-3.55 (m, 2H), 3.11-3.01 (m, 1H), 1.81 (t, J=5.6, 1H), 0.85 (s, 9H).

2-Bromo-N-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-2-amino-3,3-dimethylbutan-1-ol.

2-Bromo-N-[(1S)-1-(hydroxymethyl)propyl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-aminobutan-1-ol. MS (ESI): masscalcd. for C₁₀H₁₄BrNO₃S 306.99 m/z found 308.0 [M+H]⁺; ¹H NMR (600 MHz,CDCl₃) δ 8.11 (dd, J=7.8, 1.7, 1H), 7.72 (dd, J=7.9, 1.3, 1H), 7.47-7.42(m, 1H), 7.42-7.37 (m, 1H), 5.41 (d, J=7.9, 1H), 3.59-3.46 (m, 2H),3.19-3.10 (m, 1H), 2.15-1.99 (m, 1H), 1.56-1.38 (m, 2H), 0.78 (t, J=7.5,3H).

tert-Butyl(3S)-3-{[(2-bromophenyl)sulfonyl]amino}pyrrolidine-1-carboxylate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl3-aminopyrrolidine-1-carboxylate. MS (ESI): mass calcd. forC₁₅H₂₁BrN₂O₄S 404.04 m/z found 427.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.17-8.11 (m, 1H), 7.77-7.69 (m, 1H), 7.51-7.45 (m, 1H), 7.45-7.39 (m,1H), 5.38-5.29 (m, 1H), 3.87-3.75 (m, 1H), 3.46-3.32 (m, 2H), 3.32-3.21(m, 1H), 3.16-3.05 (m, 1H), 2.05-1.68 (m, 2H), 1.39 (s, 9H).

2-Bromo-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol. MS (ESI): mass calcd. forC₁₅H₁₄BrNO₃S 366.99 m/z found 390.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.21 (dd, J=7.7, 1.8, 1H), 7.80 (dd, J=7.8, 1.3, 1H), 7.52-7.47 (m, 1H),7.47-7.43 (m, 1H), 7.25-7.21 (m, 1H), 7.21-7.13 (m, 3H), 5.61 (d, J=6.8,1H), 4.58-4.47 (m, 1H), 4.44-4.37 (m, 1H), 3.26 (dd, J=15.9, 7.7, 1H),3.13 (d, J=2.7, 1H), 2.84-2.73 (m, 1H).

2-Bromo-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol.

2-Bromo-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol.

2-Bromo-N-cyclopropyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU usingN-cyclopropyltetrahydro-2H-pyran-4-amine. MS (ESI): mass calcd. forC₁₄H₁₈BrNO₃S 359.02 m/z found 392.0 [M+Na]⁺; ¹H NMR (600 MHz, CDCl₃) δ8.16 (dd, J=7.9, 1.7, 1H), 7.69 (dd, J=7.9, 1.2, 1H), 7.47-7.40 (m, 1H),7.40-7.34 (m, 1H), 4.40-4.30 (m, 1H), 4.05-3.96 (m, 2H), 3.52-3.39 (m,2H), 2.34-2.25 (m, 1H), 2.16-2.06 (m, 2H), 1.85-1.75 (m, 2H), 0.64-0.56(m, 2H), 0.54-0.46 (m, 2H).

racemic {4-[(2-Bromophenyl)sulfonyl]morpholin-2-yl}methanol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using racemic morpholin-2-ylmethanol. MS(ESI): mass calcd. for C₁₁H₁₄BrNO₄S 334.98 m/z found 357.9 [M+Na]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.06 (dd, J=7.8, 1.8, 1H), 7.74 (dd, J=7.8, 1.3,1H), 7.47-7.42 (m, 1H), 7.42-7.36 (m, 1H), 3.93 (m, 1H), 3.70-3.58 (m,5H), 3.58-3.51 (m, 1H), 2.94 (m, 1H), 2.77 (m, 1H), 1.96-1.83 (m, 1H).

2-Bromo-N-pyrazin-2-ylbenzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-aminopyrazine. MS (ESI): masscalcd. for C₁₀H₈BrN₃O₂S 312.95 m/z found 313.9 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) δ 11.94 (s, 1H), 8.34 (s, 1H), 8.25-8.16 (m, 2H), 8.11 (dd,J=2.7, 1.5, 1H), 7.81 (dd, J=7.9, 1.2, 1H), 7.68-7.59 (m, 1H), 7.59-7.51(m, 1H).

N˜2˜-[(2-Bromophenyl)sulfonyl]-L-leucinamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-amino-4-methylpentanamide. MS(ESI): mass calcd. for C₁₂H₁₇BrN₂O₃S 348.01 m/z found 349.0 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.01 (dd, J=7.7, 1.8, 1H), 7.92 (d, J=8.3, 1H),7.82 (dd, J=7.8, 1.3, 1H), 7.58-7.49 (m, 2H), 7.24 (d, J=2.3, 1H), 6.97(d, J=2.2, 1H), 3.67-3.56 (m, 1H), 1.65-1.53 (m, 1H), 1.51-1.40 (m, 1H),1.35-1.25 (m, 1H), 0.79 (d, J=6.6, 3H), 0.61 (d, J=6.5, 3H).

N˜2˜-[(2-Bromophenyl)sulfonyl]glycinamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-aminoacetamide. MS (ESI): masscalcd. for C₈H₉BrN₂O₃S 291.95 m/z found 293.0 [M+H]⁺; ¹H NMR (600 MHz,DMSO-d₆) δ 8.00 (dd, J=7.7, 1.8, 1H), 7.88 (s, 1H), 7.84 (dd, J=7.8,1.3, 1H), 7.59-7.54 (m, 1H), 7.54-7.50 (m, 1H), 7.27 (s, 1H), 7.13 (s,1H), 3.51 (s, 2H).

N-α-[(2-Bromophenyl)sulfonyl]-L-phenylalaninamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-amino-3-phenylpropanamide. MS(ESI): mass calcd. for C₁₅H₁₅BrN₂O₃S 382.00 m/z found 382.9 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 7.95 (d, J=8.8, 1H), 7.71-7.65 (m, 2H),7.44-7.35 (m, 3H), 7.20-7.12 (m, 5H), 7.06 (d, J=2.2, 1H), 3.93 (m, 1H),2.91 (dd, J=13.7, 4.9, 1H), 2.77 (dd, J=13.7, 9.4, 1H).

N˜2˜-[(2-Bromophenyl)sulfonyl]-L-alaninamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-2-aminopropanamide. MS (ESI):mass calcd. for C₉H₁₁BrN₂O₃S 305.97 m/z found 307.0 [M+H]⁺; ¹H NMR (600MHz, DMSO-d₆) δ 8.01 (dd, J=7.7, 1.8, 1H), 7.86 (d, J=5.2, 1H), 7.84(dd, J=7.7, 1.3, 1H), 7.60-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7.24 (s,1H), 7.07 (s, 1H), 3.78-3.69 (m, 1H), 1.17 (d, J=7.1, 3H).

tert-Butyl N˜2˜[(2-bromophenyl)sulfonyl]-L-alpha-asparaginate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl3,4-diamino-4-oxobutanoate. MS (ESI): mass calcd. for C₁₄H₁₉BrN₂O₅S406.02 m/z found 429.0 [M+Na]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 8.04-7.99(m, 2H), 7.80 (dd, J=7.7, 1.3, 1H), 7.58-7.53 (m, 1H), 7.53-7.49 (m,1H), 7.24 (s, 1H), 7.16 (s, 1H), 4.00 (m, 1H), 2.56-2.51 (m, 1H),2.45-2.39 (m, 1H), 1.32 (s, 9H).

(2R)-2-{[(2-Bromophenyl)sulfonyl]amino}-2-phenylethanamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (R)-2-amino-2-phenylacetamide. MS(ESI): mass calcd. for C₁₄H₁₃BrN₂O₃S 367.98 m/z found 369.0 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.20 (d, J=8.8, 1H), 7.91-7.86 (m, 1H),7.76-7.71 (m, 1H), 7.58 (d, J=2.0, 1H), 7.49-7.43 (m, 2H), 7.35-7.29 (m,2H), 7.26-7.20 (m, 4H), 4.94 (d, J=8.8, 1H).

tert-Butyl-N-[(2-Bromophenyl)sulfonyl]-L-valinate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using(S)-tert-butyl-2-amino-3-methylbutanoate. ¹H NMR (600 MHz, DMSO-d₆) δ8.24 (d, J=9.6, 1H), 8.00 (dd, J=7.8, 1.7, 1H), 7.82 (dd, J=7.9, 1.3,1H), 7.58-7.54 (m, 1H), 7.54-7.48 (m, 1H), 3.45 (dd, J=9.5, 7.1, 1H),1.97 (h, J=6.8, 1H), 1.22 (s, 9H), 0.87 (d, J=6.7, 3H), 0.82 (d, J=6.8,3H).

tert-Butyl-N-[(2-Bromophenyl)sulfonyl]-L-alaninate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-tert-butyl 2-aminopropanoate. MS(ESI): mass calcd. for C₁₃H₁₈BrNO₄S 363.01 m/z found 386.0 [M+Na]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.36 (d, J=8.6, 1H), 7.99 (dd, J=7.8, 1.8, 1H),7.83 (dd, J=7.8, 1.3, 1H), 7.58-7.53 (m, 1H), 7.53-7.49 (m, 1H),3.87-3.78 (m, 1H), 1.30-1.21 (m, 12H).

(S)-1-((2-Bromophenyl)sulfonyl)pyrrolidine-3-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using (S)-pyrrolidine-3-carboxamide. MS(ESI): mass calcd. for C₁₁H₁₃BrN₂O₃S 331.98, m/z found 333.0 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.05-7.97 (dd, J=7.7, 1.9, 1H), 7.92-7.85 (dd,J=7.7, 1.5, 1H), 7.64-7.53 (m, 2H), 7.43 (s, 1H), 6.96 (s, 1H),3.57-3.50 (dd, J=9.5, 8.0, 1H), 3.46-3.39 (m, 1H), 3.37-3.27 (m, 2H),3.02-2.94 (p, J=7.8, 1H), 2.12-2.02 (m, 1H), 2.02-1.91 (m, 1H).

1-((2-Bromophenyl)sulfonyl)piperidine-4-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using piperidine-4-carboxamide. MS (ESI):mass calcd. for C₁₂H₁₅BrN₂O₃S 346.00, m/z found 347.0 [M+H]⁺; ¹H NMR(600 MHz, DMSO-d₆) δ 8.03-7.97 (dd, J=7.8, 1.8, 1H), 7.91-7.86 (dd,J=7.8, 1.3, 1H), 7.63-7.53 (m, 2H), 7.28 (s, 1H), 6.82 (s, 1H),3.72-3.62 (m, 2H), 2.83-2.73 (m, 2H), 2.27-2.17 (m, 1H), 1.79-1.70 (m,2H), 1.57-1.44 (m, 2H).

1-((2-Bromophenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 3-(trifluoromethyl)azetidin-3-ol. MS(ESI): mass calcd. for C₁₀H₉BrF₃NO₃S 358.94; m/z found 359.9 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.03-8.00 (m, 1H), 7.94-7.91 (dd, J=7.4, 1.7,1H), 7.65-7.58 (m, 3H), 4.20-4.15 (m, 2H), 4.09-4.04 (m, 2H).

1-((2-Bromophenyl)sulfonyl)-N-methylazetidine-3-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using N-methylazetidine-3-carboxamide. MS(ESI): mass calcd. for C₁₁H₁₃BrN₂O₃S 331.98; m/z found 333.0 [M+H]⁺; ¹HNMR (600 MHz, CDCl₃) δ 8.09-8.04 (dd, J=7.8, 1.8, 1H), 7.79-7.74 (dd,J=7.8, 1.3, 1H), 7.49-7.44 (m, 1H), 7.44-7.37 (m, 1H), 5.72 (s, 1H),4.25-4.13 (m, 4H), 3.29-3.16 (m, 1H), 2.89-2.77 (d, J=4.8, 3H).

6-((2-Bromophenyl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptane

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-oxa-6-azaspiro[3.3]heptane. MS(ESI): mass calcd. for C₁₁H₁₂BrNO₃S 316.97; m/z found 317.9 [M+H]⁺; ¹HNMR (600 MHz, DMSO-d₆) δ 8.00-7.96 (m, 1H), 7.91-7.88 (m, 1H), 7.63-7.56(m, 2H), 4.62 (s, 4H), 4.11 (s, 4H).

6-((2-Bromophenyl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AU using 2-thia-6-azaspiro[3.3]heptane2,2-dioxide. MS (ESI): mass calcd. for C₁₁H₁₂BrNO₄S₂ 364.94; m/z found365.9 [M+H]⁺; ¹H NMR (600 MHz, DMSO-d₆) δ 8.02-7.98 (m, 1H), 7.93-7.89(m, 1H), 7.64-7.58 (m, 2H), 4.46 (s, 4H), 4.17 (s, 4H).

N-(2-Bromophenyl)ethanesulfonamide

To a solution of 2-bromoaniline (344 mg, 2.0 mmol) in pyridine (5 mL)was slowly added ethyl-sulfonyl chloride (257 mg, 2.0 mmol) at rt andthe mixture was stirred at rt for 16 hours. The pyridine was removedunder reduced pressure and resulting residue diluted with water (30 mL)and extracted with DCM (10 mL×2). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by FCC to give the title compound (240mg, 45%). MS (ESI): mass calcd. for C₈H₁₀BrNO₂S 262.96 m/z found 264.1[M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.71 (dd, J=4.8, 1.5, 1H), 7.59 (dd,J=4.8, 1.5, 1H), 7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.77 (bs, 1H),3.14 (q, J=7.2, 2H), 1.41 (t, J=7.5, 3H).

N-(2-bromophenyl)propane-1-sulfonamide

The title compound was prepared using analogous conditions described forIntermediate DL utilizing n-propylsulfonyl chloride. MS (ESI): masscalcd. for C₉H₁₂BrNO₂S, 276.98; m/z found, 278.1 [M+H]⁺. ¹H NMR (300MHz, CDCl₃) δ 7.70 (dd, J=4.8, 1.5, 1H), 7.59 (dd, J=4.8, 1.5, 1H),7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.72 (br s, 1H), 3.15-2.94 (m,2H), 1.93-1.73 (m, 2H), 1.00 (t, J=7.4, 3H).

N-(2-Bromophenyl)-2-methylpropane-1-sulfonamide

The title compound was prepared using analogous conditions described forIntermediate DL utilizing iso-butylsulfonyl chloride. MS (ESI): masscalcd. for C₁₀H₁₄BrNO₂S, 290.99; m/z found, 292.1 [M+H]⁺. ¹H NMR (300MHz, CDCl₃) δ 7.69 (dd, J=4.8, 1.5, 1H), 7.59 (dd, J=4.8, 1.5, 1H),7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.77 (br s, 1H), 2.99 (d, J=4.2,2H), 2.38-2.25 (m, 1H), 1.07 (d, J=6.9, 6H).

1-(2-Bromophenyl)-N-methylmethanesulfonamide Step A: Sodium(2-bromophenyl)methanesulfonate

A mixture of 1-bromo-2-(bromomethyl)benzene (20 g, 0.08 mol) and Na₂SO₃(15 g, 0.12 mol) in methanol/H₂O (100 mL/100 mL) was stirred at 85°Celsius for 2.5 hours, concentrated to dryness and dried to give sodium(2-bromophenyl)methanesulfonate (34 g, crude). ¹H NMR (300 MHz, DMSO-d₆)δ 7.54 (m, 2H), 7.27 (m, 1H), 7.12 (m, 1H), 3.91 (s, 2H).

Step B: (2-Bromophenyl)methanesulfonyl chloride

To a suspension of crude sodium (2-bromophenyl)methanesulfonate (34 g)in toluene (500 mL) was added PCl₅ (34 g, 0.16 mol). The resultingmixture was stirred at 100° Celsius for 4 hours before concentrating todryness and pouring the residue onto crushed ice (150 g), stirring for 5min, and extracting with DCM (3×50 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated to dryness to give(2-bromophenyl)methanesulfonyl chloride (16.8 g, 77%). ¹H NMR (300 MHz,DMSO-d₆) δ 7.62-7.45 (m, 2H), 7.29 (m, 1H), 7.18-7.01 (m, 1H), 3.97 (s,2H).

Step C

To a solution of (2-bromophenyl)methanesulfonyl chloride (2 g, 7 mmol)in THF (15 mL) was added CH₃NH₂/H₂O (25%, 2 g, 20 mmol) at 0° Celsius.The resulting mixture was warmed up to rt, stirred for 16 hours,concentrated to dryness and purified by HPLC to give the title compound(0.8 g, 41%). MS (ESI): mass calcd. for C₈H₈BrO₂S, 262.96; m/z found,264.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.54 (m, 2H), 7.35 (m, 1H),7.22 (dd, J=7.6, 1.7, 1H), 4.53 (s, 2H), 4.10 (s, 1H), 2.72 (s, 3H).

1-(2-Bromophenyl)-N-ethylmethanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO utilizing ethylamine. MS (ESI): mass calcd. forC₉H₁₂BrNO₂S, 276.98; m/z found, 277.9 [M+H]⁺; ¹H NMR (300 MHz, CD₃OD) δ7.64 (dd, J=8.0, 1.0, 1H), 7.57 (dd, J=7.6, 1.6, 1H), 7.37 (m, 1H), 7.25(m, 1H), 4.54 (s, 2H), 3.03 (q, J=7.2, 2H), 1.12 (t, J=7.2, 3H).

1-(2-Bromophenyl)-N-(2-hydroxyethyl)methanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO utilizing ethanolamine. MS (ESI): mass calcd. forC₉H₁₂BrNO₃S, 292.97; m/z found, 294.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ7.69-7.52 (m, 2H), 7.35 (m, 1H), 7.26-7.19 (m, 1H), 4.77 (t, J=6, 1H),4.56 (s, 2H), 3.65 (t, J=6, 2H), 3.12 (t, J=6, 2H), 2.13 (br s, 1H).

(S)-1-(2-Bromophenyl)-N-(2-hydroxypropyl)methanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO utilizing (S)-3-amino-2-propanol. The product wasisolated as a x. MS (ESI): mass calcd. for C₇H₄BrF₃O₂S, 306.99; m/zfound, 307.9 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.69-7.52 (m, 2H), 7.35(m, 1H), 7.29-7.20 (m, 1H), 4.67 (s, 1H), 3.96-3.76 (m, 1H), 3.17-2.96(m, 1H), 2.95-2.74 (m, 1H), 1.90-1.63 (m, 2H), 1.15 (d, J=6.3, 3H).

(R)-1-(2-Bromophenyl)-N-(2-hydroxypropyl)methanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO utilizing (R)-3-amino-2-propanol.

(2-Bromophenyl)methanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO using ammonia. ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (d,J=7.9, 1H), 7.52 (dd, J=7.6, 1.6, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 7.04(s, 2H), 4.46 (s, 2H).

4-((2-Bromobenzyl)sulfonyl)piperazin-2-one

The title compound was prepared using analogous conditions described forIntermediate DO utilizing piperazin-2-one. The product was isolated as awhite solid. MS (ESI): mass calcd. for C₁₁H₁₃BrN₂O₃S, 331.98; m/z found,333.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.68-7.57 (m, 2H), 7.37 (m, 1H),7.29-7.21 (m, 1H), 6.93 (s, 1H), 4.55 (s, 2H), 3.90 (s, J=18.1, 2H),3.43-3.17 (m, 4H).

(1,4)-trans-1-(2-Bromophenyl)-N-(1R-4-hydroxycyclohexyl)methanesulfonamide

The title compound was prepared using analogous conditions described forIntermediate DO utilizing trans-4-aminocyclohexanol. The product wasisolated as a white solid. MS (ESI): mass calcd. for C₇H₄BrF₃O₂S,347.02; m/z found, 348.0 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.70-7.56 (m,2H), 7.37 (m, 1H), 7.26 (m, 1H), 4.55 (s, 2H), 3.54-3.42 (m, 1H),3.10-2.93 (m, 1H), 2.05-1.82 (m, 4H), 1.40-1.16 (m, 4H).

tert-Butyl (1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)carbamate

The title compound was prepared using analogous conditions described forIntermediate DO utilizing tert-butyl piperazine-1-carboxylate. Theproduct was isolated as a white solid. MS (ESI): mass calcd. forC₁₇H₂₅BrN₂O₄S, 432.07; m/z found, 454.9 [M+Na]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 7.67 (dd, J=7.9, 1.2, 1H), 7.52 (dd, J=7.7, 1.7, 1H), 7.41(m, 1H), 7.36-7.26 (m, 1H), 6.92 (d, J=7.8, 1H), 4.51 (s, 2H), 3.50 (d,J=12.2, 2H), 3.45-3.35 (m, 1H), 2.92 (t, J=11.3, 2H), 1.77 (d, J=12.5,2H), 1.45-1.30 (m, 11H).

N-(1-((2-Bromobenzyl)sulfonyl)piperidin-4-yl)acetamide Step A:1-(2-Bromobenzylsulfonyl)piperidin-4-amine.HCl

A mixture of tert-butyl(1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.15 mmol)in HCl methanol (6 N, 20 mL) was stirred at rt for 24 hours, and thenconcentrated to dryness to give1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (400 mg, 94%), which wasdirectly used for next step without any further purification. MS (ESI):mass calcd. for C₁₄H₁₉BrN₂O₃S, 332.02; m/z found, 332.9 [M+H]⁺.

Step B

To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg,0.54 mmol) and Et₃N (164 mg, 1.62 mmol) in dry DCM (20 mL) was addedacetyl chloride (85 mg, 1.1 mmol) drop-wise at rt. The reaction mixturewas stirred at rt for 2 hours before concentrating to dryness andpurifying the residue by HPLC to give the title compound (180 mg, 89%).MS (ESI): mass calcd. for C₁₄H₁₉BrN₂O₃S, 374.03; m/z found, 374.8[M+H]⁺.

1-(1-((2-Bromobenzyl)sulfonyl)piperidin-4-yl)urea

To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg,0.54 mmol) and Et₃N (164 mg, 1.62 mmol) in dry THF (20 mL) was added(COCl₂)₃ (160 mg, 0.54 mmol) at rt. The reaction mixture was stirred atrt for 1 hour, and then a solution of NH₃ in THF (4 N, 10 mL) was addeddrop-wise. The resulting mixture was stirred at rt for 5 hours,concentrated to dryness and purified by HPLC to give the title compound(140 mg, 69%). MS (ESI): mass calcd. for C₁₃H₁₈BrN₃O₃S, 375.03; m/zfound, 376.0 [M+H]⁺.

1-((2-Bromobenzyl)sulfonyl)azetidin-3-ol

The title compound was prepared using analogous conditions described forIntermediate DO utilizing 3-hydroxyazetidine. The product was isolatedas a white solid. MS (ESI): mass calcd. for C₇H₄BrF₃O₂S, 304.97; m/zfound 306.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.59 (dd, J=17.3, 7.8,2H), 7.33 (m, 1H), 7.24-7.17 (m, 1H), 4.61-4.37 (m, 3H), 4.04-3.90 (m,2H), 3.87-3.75 (m, 2H), 2.13 (br s, 1H).

(2-Bromophenyl)(tert-butyl)sulfane

To a 50 mL round-bottomed flask were added a stirbar, water (3.5 mL) andH₂SO₄ (5.0 mL, 18 M). The flask was then cooled to approximately −10°Celsius and treated with t-BuOH (0.70 mL, 7.5 mmol) followed by2-bromo-thiophenol (0.60 mL, 5.0 mmol) (drop-wise over three minutes).The resulting mixture was stirred for 24 hours with gradual warming tort. The reaction mixture was then added to a separatory funnelcontaining Et₂O and sat. NaHCO₃. The layers were mixed thoroughly andthen separated. The organic layer was washed with 1 N NaOH, dried overMgSO₄, filtered and concentrated to dryness. The resulting residue wassubjected to FCC gave the title compound (686 mg, 56%). ¹H NMR (500 MHz,DMSO-d₆) δ 7.75 (dd, J=7.8, 1.4, 1H), 7.68 (dd, J=7.6, 1.6, 1H),7.43-7.37 (m, 1H), 7.36-7.29 (m, 1H), 1.28 (s, 9H).

1-Bromo-2-(tert-butylsulfonyl)benzene

To a 20 mL vial containing 411 mg (1.43 mmol)2-bromophenyl)(tert-butyl)sulfane were added DCM (6.0 mL) and a stirbar.The vial was cooled to 0° Celsius and then charged with m-CPBA (77%, 922mg, 4.43 mmol). The resultant mixture was stirred for 22 hours withgradual warming to rt. The mixture was diluted with EtOAc, washed withaq Na₂S₂O₃ followed by 1 N NaOH, dried over MgSO₄, filtered andconcentrated to dryness. The residue was subjected to FCC to give thetitle compound (304 mg, 77%). ¹H NMR (500 MHz, CDCl₃) δ 8.09-8.02 (dd,J=7.9, 1.8, 1H), 7.79-7.74 (dd, J=7.9, 1.3, 1H), 7.50-7.45 (m, 1H),7.45-7.39 (m, 1H), 1.42-1.37 (s, 9H).

1-Bromo-2-((3-(methylsulfonyl)propyl)sulfonyl)benzene Step A:(2-Bromophenyl)(3-(methylthio)propyl)sulfane

To a solution of 1-bromo-3-chloropropane (1.2 mL, 12.0 mmol), DIPEA (2.1mL, 12.0 mmol) in DCM (50 mL) was added 2-bromobenzenethiol (1.08 mL,6.0 mmol) at 5° Celsius. The reaction mixture was warmed to rt andstirred for 4 hours. The reaction mixture was concentrated to drynessand the residue dissolved in ethanol (50 mL) and treated with NaSCH₃(1.26 g, 18.0 mmol). The resulting mixture was stirred at rt for 18 h.The ethanol was then removed under reduced pressure and the residuetaken up in DCM (100 mL) and washed with water (3×20 mL). The organicphase was dried over Na₂SO₄, filtered and concentrated to dryness togive (2-bromophenyl)(3-(methylthio)propyl)sulfane (2.3 g, crude).

Step B

The procedure to make1-bromo-2-(3-(methylsulfonyl)propylsulfonyl)benzene is analogous to theone used to make Intermediate EB utilizing(2-bromophenyl)(3-(methylthio)propyl)sulfane. MS (ESI): mass calcd. forC₁₀H₁₃BrO₄S₂, 339.94; m/z found, 340.9 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ8.19-8.12 (m, 1H), 7.83-7.75 (m, 1H), 7.59-7.46 (m, 2H), 3.65 (t, J=7.1,2H), 3.34-3.23 (m, 2H), 2.94 (s, 3H), 2.43-2.30 (m, 2H).

1-Bromo-2-(ethylsulfonyl)benzene

To a suspension of NaH (135 mg, 3.40 mmol, 60% in mineral oil) inanhydrous DMF (5 mL) was added 2-bromobenzenethiol (580 mg, 3.10 mmol)drop-wise at rt. After the resultant mixture was stirred at 20° Celsiusfor 10 min, bromoethane (670 mg, 6.10 mmol) was slowly added into themixture. The reaction mixture was stirred at 30° Celsius for 14 hours inan oil bath. The reaction was diluted with water (60 mL) and extractedwith petroleum ether (20 mL×2). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated todryness. The residue was dissolved in a mixture of methanol (10 mL) andwater (15 mL) then treated with oxone (10 g, 15 mmol) portion-wise. Thereaction mixture was stirred at 80° Celsius for 16 hours. The mixturewas cooled to rt and the methanol removed. The remaining aqueous mixturewas further diluted with water (50 mL) and extracted with DCM (20 mL×2).The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered, concentrated to dryness and purified by FCC to give the titlecompound (570 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ 8.18-8.12 (m, 1H),7.76 (dd, J=7.8, 1.5, 1H), 7.52-7.43 (m, 2H), 3.46 (q, J=7.5, 2H), 1.26(t, J=7.5, 3H).

1-Bromo-2-(propylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing 1-bromopropane. MS (ESI): mass calcd. forC₉H₁₁BrO₂S, 261.97; m/z found, 263.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.15 (dd, J=7.8, 2.1, 1H), 7.78-7.74 (m, 1H), 7.54-7.42 (m, 2H),3.45-3.37 (m, 2H), 1.80-1.67 (m, 2H), 1.02 (t, J=7.5, 3H).

1-Bromo-2-(hexylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing 1-bromohexane. MS (ESI): mass calcd. forC₁₂H₁₇BrO₂S, 304.01; m/z found, 305.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.20-8.12 (m, 1H), 7.82-7.73 (m, 1H), 7.58-7.44 (m, 2H), 3.49-3.38 (m,2H), 1.77-1.63 (m, 2H), 1.43-1.24 (m, 6H), 0.86 (t, J=6.6, 3H).

1-Bromo-2-(isopropylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing isopropyl bromide. MS (ESI): mass calcd. forC₉H₁₁BrO₂S, 261.97; m/z found, 263.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.14-8.10 (m, 1H), 7.77-7.72 (m, 1H), 7.50-7.43 (m, 2H), 3.93-3.83 (m,1H), 1.30 (d, J=6.9, 6H).

1-Bromo-2-(isobutylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing isobutyl bromide. MS (ESI): mass calcd. forC₁₀H₁₃BrO₂S, 275.98; m/z found, 277.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.19-8.14 (m, 1H), 7.78-7.73 (m, 1H), 7.55-7.42 (m, 2H), 3.34 (d, J=6.6,2H), 2.30-2.19 (m, 1H), 1.07 (d, J=6.6, 6H).

1-Bromo-2-(cyclopropylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing bromocyclopropane. MS (ESI): mass calcd. forC₉H₉BrO₂S, 259.95; m/z found, 261.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.11-8.04 (m, 1H), 7.76 (dd, J=7.8, 1.5, 1H), 7.52-7.43 (m, 2H),3.22-3.14 (m, 1H), 1.36-1.31 (m, 2H), 1.08-1.03 (m, 2H).

1-Bromo-2-(cyclobutylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing bromocyclobutane. MS (ESI): mass calcd. forC₁₀H₁₁BrO₂S, 273.97; m/z found, 275.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.13 (dd, J=7.8, 2.1, 1H), 7.73 (dd, J=7.8, 1.5, 1H), 7.53-7.38 (m, 2H),4.46 (p, J=8.1, 1H), 2.65-2.46 (m, 2H), 2.25-2.12 (m, 2H), 2.08-1.98 (m,2H).

1-Bromo-2-(cyclopentylsulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing bromocyclopentane. MS (ESI): mass calcd. forC₁₁H₁₃BrO₂S, 287.98; m/z found, 289.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.20-8.10 (m, 1H), 7.80-7.72 (m, 1H), 7.58-7.39 (m, 2H), 4.27-4.12 (m,1H), 2.12-1.97 (m, 2H), 1.93-1.75 (m, 4H), 1.70-1.57 (m, 2H).

1-Bromo-2-((trifluoromethyl)sulfonyl)benzene

The title compound was prepared using analogous conditions described forIntermediate ED utilizing trifluoroiodomethane. MS (ESI): mass calcd.for C₇H₄BrF₃O₂S, 287.91; m/z found, 289.1 [M+H]⁺. ¹H NMR (300 MHz,CDCl₃) δ 8.15-8.07 (m, 1H), 7.80-7.72 (m, 1H), 7.52-7.43 (m, 2H).

(2-(1-Methylethylsulfonamido)phenyl)boronic acid

To a solution of 2-aminophenylboronic acid hydrochloride (347 mg, 2.0mmol) in pyridine (5 mL) was slowly added chlorosulfonylisopropane (300mg, 2.1 mmol). The mixture was stirred below 20° Celsius for 14 hours,concentrated to dryness and the residue purified by FCC to give thetitle compound (280 mg, 57% yield). ¹H NMR (300 MHz, D₂O+DMSO-d₆) δ8.57-8.55 (m, 1H), 7.82-7.79 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.37 (m,2H), 7.08-7.05 (m, 1H), 3.31-3.27 (m, 1H), 1.26 (d, J=6.9, 6H).

1-((2-bromophenyl)sulfonyl)-3,3-difluoropyrrolidine

A solution of 2-bromobenzene-1-sulfonyl chloride (0.300 g, 1.17 mmol)and 3,3-difluoropyrrolidine hydrochloride (0.169 g, 1.17 mmol) inpyridine (5 mL) was stirred for 16 hours at 60° Celsius. The reactionwas then cooled to rt, diluted with EtOAc (25 mL), washed with 1 N HCl(2×25 mL), and brine (50 mL). The organic layer was isolated, dried overMgSO₄, filtered and concentrated to dryness to yield the title compound(0.335 g, 86%), The product was used without further purification. ¹HNMR (500 MHz, CDCl₃) δ 8.13-8.09 (m, 1H), 7.80-7.76 (m, 1H), 7.50-7.41(m, 2H), 3.74 (t, J=12.8, 2H), 3.67 (t, J=7.2, 2H), 2.44-2.35 (m, 2H).

1-((2-Bromophenyl)sulfonyl)-4,4-difluoropiperidine

The title compound was prepared in a manner similar to that described inIntermediate EN using 4,4-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃) δ8.13-8.11 (m, 1H), 7.78-7.75 (m, 1H), 7.50-7.45 (m, 1H), 7.44-7.39 (m,1H), 3.53-3.44 (m, 4H), 2.12-2.03 (m, 4H).

1-((2-Bromophenyl)sulfonyl)piperazine

The title compound was prepared in a manner similar to that described inIntermediate EN using piperazine.

1-((2-Bromophenyl)sulfonyl)-3,3-difluoropiperidine

The title compound was prepared in a manner similar to that described inIntermediate EN using 3,3-difluoropiperidine. ¹H NMR (500 MHz, CDCl₃) δ8.14-8.11 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.44 (m, 1H), 7.44-7.39 (m,1H), 3.54 (t, J=11.2, 2H), 3.32 (t, J=5.5, 2H), 2.04-1.94 (m, 2H),1.91-1.85 (m, 2H).

1-((2-Bromophenyl)sulfonyl)-3,3-difluoroazetidine

The title compound was prepared in a manner similar to that described inIntermediate EN using 3,3-difluoroazetidine. ¹H NMR (500 MHz, CDCl₃) δ8.11-8.06 (m, 1H), 7.80-7.76 (m, 1H), 7.50-7.42 (m, 2H), 4.42 (t,J=12.1, 4H).

1-((2-Bromophenyl)sulfonyl)azepane

The title compound was prepared in a manner similar to that described in

1-((2-Bromophenyl)sulfonyl)-4-(trifluoromethyl)piperidin-4-ol

The title compound was prepared in a manner similar to that described inIntermediate EN using 4-(trifluoromethyl)piperidin-4-ol.

tert-Butyl (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)carbamate

A solution of 2-bromobenzene-1-sulfonyl chloride (50 mg, 0.20 mmol),tert-butyl piperidin-4-ylcarbamate (49 mg, 0.25 mmol), anddiisopropylethyl amine (0.101 mL, 0.59 mmol) in CH₂Cl₂ was stirred for90 min at rt. The reaction mixture was then concentrated to dryness togive the title compound in quantitative yield. The product was usedwithout further purification.

racemic tert-butyl (1-((2-Bromophenyl)sulfonyl)piperidin-3-yl)carbamate

The title compound was prepared in a manner similar to that described inIntermediate EU using racemic tert-butyl piperidin-3-ylcarbamate. ¹H NMR(400 MHz, CDCl₃) δ 8.12-8.09 (m, 1H), 7.77-7.74 (m, 1H), 7.48-7.38 (m,2H), 4.91 (d, J=8.0, 1H), 3.79 (s, 1H), 3.45 (s, 1H), 3.32 (d, J=12.4,1H), 3.23-3.07 (m, 2H), 1.86-1.59 (m, 4H), 1.45 (s, 9H).

racemic 1-((2-Bromophenyl)sulfonyl)piperidin-3-amine hydrochloride salt

A solution of racemic tert-butyl(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate (82 mg, 0.20 mmol)in CH₂Cl₂ (5 mL) was treated with 2 N HCl/Et₂O (1 mL, 2 mmol) andstirred 16 hours at rt. The reaction mixture was then concentrated todryness to give the title compound in quantitative yield. The productwas used without further purification.

1-((2-Bromophenyl)sulfonyl)piperidin-4-amine hydrochloride

The title compound was prepared in a manner similar to that described inIntermediate EW using tert-butyl(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)carbamate.

1-((2-Bromophenyl)sulfonyl)-4-(methylsulfonyl)piperazine

The title compound was prepared in a manner similar to that described inIntermediate EU using 1-(methylsulfonyl)piperazine.

1-(4-((2-Bromophenyl)sulfonyl)piperazin-1-yl)ethanone

The title compound was prepared in a manner similar to that described inIntermediate EU using 1-(piperazin-1-yl)ethanone.

(4-((2-Bromophenyl)sulfonyl)piperazin-1-yl)(cyclopropyl)methanone

The title compound was prepared in a manner similar to that described inIntermediate EU using cyclopropyl(piperazin-1-yl)methanone.

2-(4-((2-Bromophenyl)sulfonyl)piperazin-1-yl)ethanol

The title compound was prepared in a manner similar to that described inIntermediate EU using 2-(piperazin-1-yl)ethanol.

1-((2-Bromophenyl)sulfonyl)-4-cyclopropylpiperazine

The title compound was prepared in a manner similar to that described inIntermediate EU using 1-cyclopropylpiperazine.

Racemic-2-((2-Bromophenyl)sulfonyl)octahydropyrrolo[1,2-a]pyrazine

The title compound was prepared in a manner similar to that described inIntermediate EU using racemic-octahydropyrrolo[1,2-a]pyrazine.

4-((2-Bromophenyl)sulfonyl)piperazin-2-one

The title compound was prepared in a manner similar to that described inIntermediate EU using piperazin-2-one.

Racemic-1-((2-bromophenyl)sulfonyl)piperidine-3-carbonitrile

The title compound was prepared in a manner similar to that described inIntermediate EU using racemic-piperidine-3-carbonitrile.

1-((2-Bromophenyl)sulfonyl)piperidine-4-carbonitrile

The title compound was prepared in a manner similar to that described inIntermediate EU using piperidine-4-carbonitrile.

1-((2-Bromophenyl)sulfonyl)-4-methylpiperazine

The title compound was prepared in a manner similar to that described inIntermediate EU using 1-methylpiperazine.

N-(1-((2-Bromophenyl)sulfonyl)piperidin-4-yl)acetamide

A solution of 2-bromobenzene-1-sulfonyl chloride (0.500 g, 1.96 mmol),4-acetamidopiperidine (0.335 g, 2.45 mmol), and diisopropylethyl amine(1.0 mL, 5.8 mmol) in CH₂Cl₂ (5 mL) was stirred for 15 min at rt. Thereaction mixture was then washed with 1 N HCl (2×5 mL) followed by brine(10 mL). The organic layer was isolated, dried over MgSO₄, filtered, andconcentrated to dryness to give the title compound (0.672 g, 95%). Theproduct was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ8.09-8.05 (m, 1H), 7.77-7.74 (m, 1H), 7.49-7.38 (m, 2H), 6.08 (d, J=8.0,1H), 3.87-3.79 (m, 2H), 2.93-2.85 (m, 2H), 2.00-1.93 (m, 5H), 1.59-1.51(m, 3H).

1-((2-Bromophenyl)sulfonyl)piperidin-4-ol

The title compound was prepared in a manner similar to that described inIntermediate FI using piperidin-4-ol. ¹H NMR (400 MHz, CDCl₃) δ8.11-8.07 (m, 1H), 7.77-7.73 (m, 1H), 7.48-7.36 (m, 2H), 3.92-3.84 (m,1H), 3.65-3.55 (m, 2H), 3.18-3.11 (m, 2H), 1.99-1.88 (m, 2H), 1.69-1.59(m, 2H).

(1-((2-Bromophenyl)sulfonyl)piperidin-4-yl)methanol

The title compound was prepared in a manner similar to that described inIntermediate FI using piperidin-4-ylmethanol. ¹H NMR (400 MHz, CDCl₃) δ8.11-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.36 (m, 2H), 3.90-3.84 (m,2H), 3.50 (d, J=6.4, 2H), 2.82-2.73 (m, 2H), 1.79-1.84 (m, 2H),1.67-1.56 (m, 1H), 1.37-1.24 (m, 2H).

2-(1-((2-Bromophenyl)sulfonyl)piperidin-4-yl)ethanol

The title compound was prepared in a manner similar to that described inIntermediate FI using 2-(piperidin-4-yl)ethanol. ¹H NMR (400 MHz, CDCl₃)δ 8.10-8.06 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.36 (m, 2H), 3.86-3.79 (m,2H), 3.68 (t, J=6.3, 2H), 2.80-2.72 (m, 2H), 1.78-1.71 (m, 2H),1.56-1.51 (m, 3H), 1.37-1.23 (m, 2H).

Racemic-1-((2-Bromophenyl)sulfonyl)piperidin-3-ol

The title compound was prepared in a manner similar to that described inIntermediate FI using racemic piperidin-3-ol. ¹H NMR (400 MHz, CDCl₃) δ8.13-8.09 (m, 1H), 7.77-7.73 (m, 1H), 7.50-7.37 (m, 2H), 3.89-3.82 (m,1H), 3.57-3.51 (m, 1H), 3.40-3.32 (m, 1H), 3.24-3.16 (m, 1H), 3.06-3.00(m, 1H), 2.16 (s, 1H), 1.94-1.80 (m, 2H), 1.70-1.50 (m, 2H).

racemic (1-((2-Bromophenyl)sulfonyl)piperidin-3-yl)methanol

The title compound was prepared in a manner similar to that described inIntermediate FI using racemic piperidin-3-ylmethanol. ¹H NMR (400 MHz,CDCl₃) δ 8.11-8.07 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.36 (m, 2H),3.76-3.51 (m, 4H), 3.02-2.94 (m, 1H), 2.83-2.75 (m, 1H), 1.94-1.84 (m,1H), 1.82-1.71 (m, 3H), 1.67-1.57 (m, 1H), 1.29-1.17 (m, 1H).

racemic 2-(1-((2-Bromophenyl)sulfonyl)piperidin-3-yl)ethanol

The title compound was prepared in a manner similar to that described inIntermediate FI using racemic 2-(piperidin-3-yl)ethanol. ¹H NMR (400MHz, CDCl₃) δ 8.10-8.06 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.36 (m, 2H),3.72-3.62 (m, 4H), 2.88-2.80 (m, 1H), 2.60-2.53 (m, 1H), 1.89-1.39 (m,7H), 1.16-1.03 (m, 1H).

4-((2-Bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide

The title compound was prepared in a manner similar to that described inIntermediate FI using thiomorpholine 1,1-dioxide. ¹H NMR (400 MHz,CDCl₃) δ 8.17-8.11 (m, 1H), 7.81-7.76 (m, 1H), 7.53-7.43 (m, 2H),3.92-3.86 (m, 4H), 3.24-3.13 (m, 4H).

2-Bromo-N-((1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (1S,2S)-2-amino-1-phenylpropane-1,3-diol.

(S)-2-Bromo-N-(1-hydroxy-4-methyl pentan-2-yl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (S)-2-amino-4-methylpentan-1-ol.

2-Bromo-N-(3-hydroxypropyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using 3-aminopropan-1-ol

(S)-2-Bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (S)-2-amino-2-phenylethanol.

(R)-2-Bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (R)-2-amino-2-phenylethanol

2-Bromo-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (1R,2S)-2-amino-1-phenylpropan-1-ol.

2-Bromo-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (2S,3S)-2-amino-3-methylpentan-1-ol.

2-Bromo-N-((1R,2R)-2-hydroxycyclohexyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (1R,2R)-2-aminocyclohexanol.

2-Bromo-N-((1R,2S)-2-hydroxycyclohexyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (1S,2R)-2-aminocyclohexanol

(R)-2-Bromo-N-(1-hydroxybutan-2-yl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inIntermediate FI using (R)-2-aminobutan-1-ol.

Racemic-1-((2-Bromophenyl)sulfonyl)-3,5-dimethylpiperazine

A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol),2,6-dimethylpiperazine (56 mg, 0.49 mmol), and diisopropylethyl amine(0.202 mL, 1.17 mmol) in CH₂Cl₂ (2.5 mL) was allowed to stir for 15 minat rt. The reaction mixture was then directly subjected to FCCpurification to give the title compound (0.105 g, 81%). ¹H NMR (600 MHz,CDCl₃) δ 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H),7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m,2H), 1.06-1.04 (m, 6H).

1-((2-Bromophenyl)sulfonyl)-N-methylpiperidin-4-amine

The title compound was prepared in a manner similar to that described inIntermediate EU using N-methylpiperidin-4-amine.

1-((2-Bromophenyl)sulfonyl)-N,N-dimethylpiperidin-4-amine

The title compound was prepared in a manner similar to that described inIntermediate EU using N,N-dimethylpiperidin-4-amine.

2-Bromo-N-(1-(hydroxymethyl)cyclopentyl)benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using cycloleucinol. ¹H NMR (500 MHz,CDCl₃) δ 8.16 (dd, J=7.8, 1.8, 1H), 7.75 (dd, J=7.9, 1.3, 1H), 7.51-7.45(m, 1H), 7.44-7.39 (m, 1H), 5.25 (s, 1H), 4.23 (s, 1H), 3.59 (d, J=6.4,2H), 2.36 (t, J=6.5, 1H), 1.90-1.78 (m, 1H), 1.77-1.60 (m, 4H),1.56-1.49 (m, 2H).

1-((2-Bromophenyl)sulfonyl)-3-phenylpyrrolidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using 3-phenyl-3-pyrrolidinol. ¹H NMR (500MHz, CDCl₃) δ 8.17 (dd, J=7.8, 1.8, 1H), 7.77 (dd, J=7.8, 1.3, 1H),7.49-7.43 (m, 3H), 7.43-7.34 (m, 3H), 7.34-7.27 (m, 1H), 3.82-3.75 (m,3H), 3.71 (d, J=10.8, 1H), 2.46-2.37 (m, 1H), 2.29-2.23 (m, 1H), 2.15(s, 1H).

(R)-1-((2-Bromophenyl)sulfonyl)pyrrolidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using (R)-3-hydroxypyrrolidine. ¹H NMR (500MHz, CDCl₃) δ 8.13 (dd, J=7.8, 1.7, 1H), 7.75 (dd, J=7.8, 1.3, 1H),7.48-7.42 (m, 1H), 7.39 (m, 1H), 4.57-4.47 (m, 1H), 3.63-3.51 (m, 3H),3.48-3.40 (m, 1H), 2.14-2.04 (m, 1H), 2.04-1.94 (m, 1H), 1.94-1.84 (m,1H).

(S)-1-((2-Bromophenyl)sulfonyl)pyrrolidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using (S)-3-hydroxypyrrolidine. ¹H NMR (500MHz, CDCl₃) δ 8.12 (dd, J=7.8, 1.7, 1H), 7.75 (dd, J=7.8, 1.3, 1H), 7.45(m, 1H), 7.39 (m, 1H), 4.56-4.46 (m, 1H), 3.65-3.50 (m, 3H), 3.44 (m,1H), 2.13-2.03 (m, 1H), 2.03-1.87 (m, 2H).

(Racemic)-1′-((2-Bromophenyl)sulfonyl)-[1,3′-bipyrrolidin]-4′-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using (racemic)-[1,3′-bipyrrolidin]-4′-ol.¹H NMR (500 MHz, CDCl₃) δ 8.12 (dd, J=7.8, 1.8, 1H), 7.75 (dd, J=7.8,1.3, 1H), 7.48-7.34 (m, 2H), 4.42-4.29 (m, 1H), 3.74 (m, 2H), 3.36 (m,2H), 2.83 (dd, J=10.9, 6.3, 1H), 2.70-2.43 (m, 4H), 1.83-1.66 (m, 4H).

Racemic 1-((2-Bromophenyl)sulfonyl)-4-morpholinopyrrolidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM using Racemic-4-morpholinopyrrolidin-3-ol.¹H NMR (500 MHz, CDCl₃) δ 8.11 (dd, J=7.8, 1.8, 1H), 7.76 (dd, J=7.8,1.3, 1H), 7.49-7.44 (m, 1H), 7.44-7.38 (m, 1H), 4.35 (t, J=7.4, 1H),3.78-3.70 (m, 2H), 3.70-3.67 (m, 4H), 3.35-3.26 (m, 2H), 2.89 (m, 1H),2.65-2.56 (m, 2H), 2.52-2.44 (m, 2H).

Racemic-1-((2-Bromophenyl)sulfonyl)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate AM usingRacemic-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol. ¹H NMR (500 MHz,CDCl₃) δ 8.10 (dd, J=7.8, 1.8, 1H), 7.76 (dd, J=7.8, 1.3, 1H), 7.51-7.37(m, 2H), 4.37 (dd, J=12.1, 5.8, 1H), 3.81-3.65 (m, 2H), 3.29 (m, 2H),2.99 (dd, J=13.1, 7.3, 1H), 2.91-2.57 (m, 8H), 2.45 (s, 3H).

4-((2-Bomophenyl)sulfonyl)piperazin-2-one

The title compound was prepared using analogous conditions to thosedescribed in Intermediate EU using 2-bromobenzene-1-sulfonyl chlorideand piperazin-2-one. MS (ESI): mass calcd. for C₁₀H₁₁BrN₂O₃S, 317.96;m/z found, 319.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (s, 1H),8.09-8.00 (m, 1H), 7.93-7.89 (m, 1H), 7.62 (m, 2H), 3.79 (s, 2H),3.50-3.43 (m, 2H), 3.18 (m, 2H).

2-Bromo-N-(2-hydroxyethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 2-aminoethanol. ¹H NMR (500 MHz, CDCl₃) δ8.17-8.11 (dd, J=7.8, 1.8, 1H), 7.79-7.72 (dd, J=7.8, 1.3, 1H),7.52-7.46 (m, 1H), 7.46-7.40 (m, 1H), 5.79-5.66 (t, J=5.7, 1H),3.73-3.65 (dd, J=5.6, 4.6, 2H), 3.13-3.03 (m, 2H), 2.14 (s, 1H).

(R)-(1-((2-Bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (R)-pyrrolidin-2-ylmethanol. ¹H NMR (500 MHz,CDCl₃) δ 8.25-8.04 (m, 1H), 7.86-7.70 (m, 1H), 7.54-7.45 (m, 1H),7.45-7.39 (m, 1H), 4.11-3.96 (m, 1H), 3.75-3.57 (m, 2H), 3.58-3.46 (dd,J=10.8, 4.5, 1H), 3.46-3.36 (m, 1H), 2.91-2.39 (m, 1H), 2.14-1.85 (m,3H), 1.85-1.74 (dd, J=10.7, 5.3, 1H).

(S)-(1-((2-Bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (S)-pyrrolidin-2-ylmethanol. ¹H NMR (500 MHz,CDCl₃) δ 8.18-8.07 (dd, J=7.9, 1.8, 1H), 7.81-7.70 (dd, J=7.9, 1.3, 1H),7.52-7.45 (m, 1H), 7.45-7.38 (m, 1H), 4.08-3.92 (m, 1H), 3.70-3.56 (m,2H), 3.55-3.45 (m, 1H), 3.45-3.35 (m, 1H), 2.76-2.67 (t, J=6.1, 1H),2.03-1.87 (m, 3H), 1.84-1.74 (m, 1H).

(R)-2-Bromo-N-(2-hydroxypropyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (R)-1-aminopropan-2-ol. ¹H NMR (500 MHz,CDCl₃) δ 8.17-8.09 (dd, J=7.8, 1.8, 1H), 7.81-7.71 (dd, J=7.8, 1.3, 1H),7.51-7.46 (m, 1H), 7.46-7.40 (m, 1H), 5.65-5.60 (t, J=6.1, 1H),3.98-3.81 (m, 1H), 3.08-2.96 (m, 1H), 2.85-2.58 (m, 1H), 2.04-2.02 (d,J=4.3, 1H), 1.18-1.14 (d, J=6.3, 3H).

(S)-2-Bromo-N-(2-hydroxypropyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (S)-1-aminopropan-2-ol. ¹H NMR (500 MHz,CDCl₃) δ 8.21-8.04 (dd, J=7.8, 1.8, 1H), 7.78-7.72 (dd, J=7.8, 1.3, 1H),7.53-7.46 (m, 1H), 7.46-7.38 (m, 1H), 5.71-5.54 (d, J=5.9, 1H),3.97-3.84 (m, 1H), 3.07-2.96 (m, 1H), 2.80-2.69 (m, 1H), 2.03-1.95 (d,J=4.4, 1H), 1.19-1.07 (d, J=6.3, 3H).

2-Bromo-N-((1-hydroxycyclohexyl)methyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 1-(aminomethyl)cyclohexanol. ¹H NMR (500 MHz,CDCl₃) δ 8.17-8.09 (dd, J=7.8, 1.8, 1H), 7.78-7.70 (dd, J=7.8, 1.3, 1H),7.51-7.45 (m, 1H), 7.45-7.39 (m, 1H), 5.56-5.45 (t, J=6.3, 1H), 3.71 (s,1H), 2.89-2.77 (d, J=6.4, 2H), 1.60-1.28 (m, 10H).

(S)-tert-Butyl (1-((2-bromophenyl)sulfonyl)pyrrolidin-3-yl)carbamate

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (S)-tert-butyl pyrrolidin-3-ylcarbamate. ¹HNMR (500 MHz, CDCl₃) δ 8.17-8.06 (dd, J=7.8, 1.8, 1H), 7.81-7.67 (dd,J=7.8, 1.3, 1H), 7.49-7.43 (m, 1H), 7.43-7.37 (m, 1H), 4.73 (s, 1H),4.25 (s, 1H), 3.65-3.51 (d, J=8.8, 2H), 3.51-3.43 (m, 1H), 3.37-3.20(dd, J=10.0, 3.8, 1H), 2.33-2.12 (m, 1H), 1.98-1.81 (dd, J=12.8, 6.9,1H), 1.43 (s, 9H).

(R)-tert-Butyl (1-((2-bromophenyl)sulfonyl)pyrrolidin-3-yl)carbamate

The title compound was prepared in a manner similar to that describedfor Intermediate EU using (R)-tert-butyl pyrrolidin-3-ylcarbamate. ¹HNMR (500 MHz, CDCl₃) δ 8.15-8.10 (dd, J=7.8, 1.8, 1H), 7.79-7.73 (dd,J=7.8, 1.3, 1H), 7.49-7.43 (m, 1H), 7.43-7.37 (m, 1H), 4.73 (s, 1H),4.25 (s, 1H), 3.65-3.52 (m, 2H), 3.51-3.43 (m, 1H), 3.34-3.22 (m, 1H),2.25-2.13 (m, 1H), 1.95-1.82 (dd, J=12.6, 7.0, 1H), 1.43 (s, 9H).

2-(4-((2-Bromophenyl)sulfonyl)piperazin-1-yl)pyrazine

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 2-(piperazin-1-yl)pyrazine. ¹H NMR (500 MHz,CDCl₃) δ 8.16-8.09 (m, 2H), 8.07-8.02 (dd, J=2.6, 1.5, 1H), 7.90-7.87(d, J=2.6, 1H), 7.78-7.74 (dd, J=7.9, 1.3, 1H), 7.51-7.45 (m, 1H),7.44-7.37 (m, 1H), 3.74-3.58 (m, 4H), 3.48-3.38 (m, 4H).

2-(4-((2-Bromophenyl)sulfonyl)piperazin-1-yl)pyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 2-(piperazin-1-yl)pyrimidine. ¹H NMR (500 MHz,CDCl₃) δ 8.33-8.27 (d, J=4.7, 2H), 8.15-8.06 (dd, J=7.9, 1.7, 1H),7.78-7.71 (dd, J=7.9, 1.3, 1H), 7.50-7.43 (m, 1H), 7.43-7.36 (m, 1H),6.57-6.43 (t, J=4.7, 1H), 3.98-3.78 (m, 4H), 3.42-3.31 (m, 4H).

2-Bromo-N-methyl-5-(trifluoromethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using methylamine and2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,CDCl₃) δ 8.46-8.29 (d, J=2.4, 1H), 7.99-7.79 (d, J=8.3, 1H), 7.79-7.59(dd, J=8.3, 2.3, 1H), 5.20-5.01 (d, J=6.4, 1H), 2.80-2.56 (d, J=5.3,3H).

2-Bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using ethylamine and2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,CDCl₃) δ 8.43-8.38 (m, 1H), 7.93-7.86 (dd, J=8.3, 0.9, 1H), 7.70-7.62(m, 1H), 5.08 (s, 1H), 3.11-2.96 (m, 2H), 1.19-1.09 (t, J=7.2, 3H).

2-Bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 2-aminoethanol and2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,CD₃OD) δ 8.35-8.30 (m, 1H), 8.07-7.98 (dd, J=8.2, 0.9, 1H), 7.82-7.76(m, 1H), 3.59-3.50 (t, J=5.9, 2H), 3.10-3.02 (t, J=5.9, 2H).

1-((2-Bromo-5-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine

The title compound was prepared in a manner similar to that describedfor Intermediate EU using 1-methylpiperazine and2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (500 MHz,CDCl₃) δ 8.37-8.28 (d, J=2.2, 1H), 7.98-7.86 (d, J=8.2, 1H), 7.73-7.59(d, J=8.2, 1H), 3.45-3.31 (t, J=5.0, 4H), 2.60-2.42 (t, J=4.9, 4H),2.40-2.20 (d, J=1.5, 3H).

4-((2-Bromo-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-2-one

The title compound was prepared in a manner similar to that describedfor Intermediate EU using piperazin-2-one and2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. ¹H NMR (400 MHz,CDCl₃) δ 8.43-8.35 (d, J=2.3, 1H), 7.99-7.89 (d, J=8.2, 1H), 7.77-7.65(dd, J=8.3, 2.3, 2H), 6.95 (s, 2H), 3.99 (s, 3H), 3.73-3.58 (t, J=5.3,3H), 3.51-3.42 (m, 3H), 1.36-1.04 (m, 1H).

5-(4-Chloro-2-fluorophenyl)pyrimidin-2-amine

To a 500 mL round-bottomed flask were added 5-bromo-2-aminopyrimidine(4.0 g, 23 mmol), 4-chloro-2-fluorophenylboronic acid (3.9 g, 23 mmol),palladium(II)trifluoroacetate (240 mg, 0.72 mmol), and triphenylphoshine(373 mg, 1.40 mmol). The reaction vessel was fitted with a rubberseptum, sparged with nitrogen and then charged with sparged toluene (75mL), ethanol (75 mL), and a 2M solution of sodium carbonate (42 mL, 84mmol) (solvents were sparged individually nitrogen gas for 30 minutes).The resulting mixture was stirred vigorously and heated at 50° Celsius.After 12 hours, the mixture was cooled to rt and treated with 100 mL ofwater. The precipitate was isolated via vacuum filtration, and thefiltrate extracted with EtOAC. The EtOAc solution was dried, filteredand concentrated to dryness. The resultant solids were recrystallizedfrom IPA (80 mL) to afford title compound (3.8 g, 74%). MS (ESI): masscalcd. for C₁₀H₇ClFN₃, 223.03; m/z found, 224.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.44 (d, J=1.4, 2H), 7.59 (m, 1H), 7.54 (dd, J=10.7, 2.1,1H), 7.37 (dd, J=8.3, 2.1, 1H), 6.94 (s, 2H).

5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine

Nitrogen sparged 1,4-dioxane (80 mL) was added to a 250 mLround-bottomed flask containing4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.1 g, 8.4mmol), 5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine (1.5 g, 6.7 mmol),chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1-1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(X-Phos pre-catalyst) (0.1 g, 0.13 mmol), and potassium acetate (1.9 g,20 mmol). The reaction mixture was heated at 80° Celsius for 4 hoursbefore cooling to rt, concentrating to dryness, and the residuesubjected to FCC to provide the title compound (1.8 g, 83%). MS (ESI):mass calcd. for C₁₆H₁₉BFN₃O₂, 315.15; m/z found, 316.4 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.53 (d, J=1.3 Hz, 2H), 7.64 (dd, J=7.6, 1.0 Hz, 1H),7.58 (dd, J=11.0, 0.9 Hz, 1H), 7.38 (m, 1H), 5.23 (s, 2H), 1.36 (s,12H).

Example 1

5-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine Method 1

To a 100 mL round-bottomed flask were added a stirbar,5-(4-bromo-2-fluorophenyl)pyrazin-2-amine, (3.639 g, 13.57 mmol)(2-(methylsulfonyl)-phenyl)boronic acid (4.076 g, 20.38 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (1.136 g, 1.391 mmol) and K₂CO₃ (5.663 g, 40.97mmol). The flask was flushed with nitrogen and then charged with 56.0 mLthoroughly sparged (1 hour of bubbling N₂) DMSO. The flask was heated at80° Celsius for 5.25 hours before cooling to room temperature, dilutingthe reaction mixture with EtOAc and filtering the mixture through a padof celite. The filtrate was washed twice with 1 N NaOH and the organiclayer dried over MgSO₄. Filtering and concentrating the filtrate todryness gave the crude product. The soluble portion of the residue wasthen subjected to FCC to give the title compound. (3.80 g, 81%).

Method 2 Step A: 5-(4-Chloro-2-fluorophenyl)pyrazin-2-amine

To a nitrogen flushed flask containing 4-chloro-2-fluorobenzene boronicacid (40.0 g, 229 mmol), 2-amino-5-bromopyrazine (39.9 g, 229 mmol),palladium(II) trifluoroacetate (1.5 g, 4.6 mmol), and triphenylphosphine(2.4 g, 9.2 mmol) were added sparged toluene (750 mL), ethanol (750 mL),and 2 M Na₂CO_(3(aq)) (418 mL, 836 mmol). The mixture was stirred andheated at 50° Celsius for 15 hours and then cooled to rt. Water (750 mL)was added and the layers were separated. The aqueous layer was washedwith ethyl acetate (750 mL). The combined organic layers were washedwith brine (500 mL), dried over Na₂SO₄, filtered, and concentrated todryness to give 55.4 g of crude product. The crude solid wascrystallized from toluene (450 mL) to provide the title compound (40.0g, 78%). MS (ESI): mass calcd. for C₁₀H₇ClFN₃, 223.03; m/z found, 224.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.03 (d,J=1.6, 1H), 7.89 (m, 1H), 7.52 (dd, J=11.3, 2.1, 1H), 7.38 (dd, J=8.5,2.1, 1H), 6.79 (s, 2H).

Step B:5-(3-Fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

To a nitrogen sparged flask containing5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (34.0 g, 152 mmol),2-methylsulfonylphenylboronic acid (38.0 g, 190 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.39 g, 3.0 mmol) were added sparged THF (300 mL) and K₃PO_(4(aq)) (608mL, 0.5 M). The mixture was stirred for 15 hours at rt and thenconcentrated under reduced pressure to remove the THF. The remainingportion was treated with toluene (325 mL) and THF (25 mL). The biphasicslurry was stirred for 20 h at rt and then filtered and the isolatedsolid washed with water (150 mL) and toluene (150 mL). The filter cakewas dried to provide the title compound (47.1 g, 90%). MS (ESI): masscalcd. for C₁₇H₁₄FN₃O₂S, 343.08; m/z found, 344.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.41 (dd, J=2.4, 1.5, 1H), 8.12 (dd, J=7.9, 1.4, 1H),8.04 (d, J=1.5, 1H), 7.93 (m, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.48 (dd,J=7.6, 1.4, 1H), 7.37 (dd, J=12.3, 1.7, 1H), 7.32 (dd, J=8.1, 1.7, 1H),6.76 (s, 2H), 2.95 (s, 3H).

Example 2

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using (2-(methylsulfonamido)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₇H₁₅FN₄O₂S, 358.09; m/z found, 359.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.40 (dd, J=2.3, 1.4, 1H),8.04 (d, J=1.5, 1H), 7.97-7.89 (m, 1H), 7.50-7.34 (m, 6H), 6.71 (s, 2H),2.84 (s, 3H).

Example 3

6-Amino-3-[3-fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using 2-(methylsulfonyl)phenylboronic acid and5-(4-bromo-2-fluorophenyl)-6-cyanopyrazin-2-amine. MS (ESI): mass calcd.for C₁₈H₁₃FN₄O₂S, 368.07; m/z found, 369.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.26 (s, 1H), 8.13 (dd, J=8.0, 1.4, 1H), 7.84-7.77 (m, 1H),7.76-7.70 (m, 1H), 7.69-7.62 (m, 1H), 7.51 (dd, J=7.6, 1.4, 1H), 7.46(dd, J=11.0, 1.6, 1H), 7.42-7.35 (m, 3H), 2.97 (s, 3H).

Example 4

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronicacid. MS (ESI): mass calcd. for C₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (dd, J=2.2, 1.4, 1H), 8.09-8.02(m, 2H), 7.93-7.87 (m, 1H), 7.68-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.38(dd, J=7.5, 1.4, 1H), 7.33-7.26 (m, 2H), 6.94 (s, 1H), 6.71 (s, 2H),1.02 (s, 9H).

Example 5

4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide Method 1

To a 50 mL round-bottomed flask were added 1.071 g (2.67 mmol)4′-(5-aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide, astirbar and 20 mL TFA. The mixture was heated at 50° Celsius for 2 hoursand then carefully and slowly added to 300 mL rapidly stirring sat.NaHCO₃. The resulting mixture was stirred for 30 min and then the solidwas isolated via vacuum filtration. The solid was washed with 200 mLdeionized water, air dried and then further dried under high vacuum withgentle heating to give the title compound (751 mg, 82%).

Method 2 Step A:4′-(5-Aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

To a nitrogen flushed flask containing5-(4-chloro-2-fluorophenyl)pyrazin-2-amine (82.8 g, 370 mmol),(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid (100.0 g, 388.9 mmol),andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(5.83 g, 7.41 mmol) were added N₂ sparged THF (926 mL) and sparged 0.5 MK₃PO_(4(aq)) (1.65 L, 825 mmol). The mixture was stirred for 15 hours atroom temperature. The layers were separated and the organic layer waswashed with 600 mL brine, dried over MgSO₄, filtered, and concentratedto dryness to give a solid residue. The solid was dissolved in 900 mLDMA, stirred with 60 g activated charcoal at 80° Celsius for 2 hours,and then stirred at room temperature for an additional 16 hours. Thecharcoal was removed by filtration and then washed with 150 mL DMA. Thecombined filtrates were treated three times with fresh Silicycle brandSiliaMetS Thiol Pd Scavenger (30 g, 15 g, 7.5 g) in DMA at 80° Celsiusfor 8 hours to 16 hours. Upon cooling to rt the scavenger was filteredoff and the filtrate was concentrated to dryness. The resulting solidwas triturated in toluene (1.2 L) at 90° Celsius for 2 hours. Uponcooling to rt the solid was collected by filtration and washed twicewith toluene (700 mL) and twice with hexanes (700 mL) yielding the titlecompound (120.0 g, 80.9%). MS (ESI): mass calcd. for C₂₀H₂₁FN₄O₂S,400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.42-8.37(m, 1H), 8.10-8.02 (m, 2H), 7.95-7.86 (m, 1H), 7.70-7.63 (m, 1H),7.63-7.58 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.26 (m, 2H), 7.00-6.92 (s,1H), 6.79-6.66 (s, 2H), 1.10-0.95 (s, 9H).

Step B: 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

A solution of4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide(130.0 g, 298.0 mmol), anisole (97.4 mL, 894.0 mmol), and TFA (228.0 mL,2.98 mol) was stirred at 60° Celsius for 16 hours. The reaction wascooled to rt, concentrated to dryness, and partitioned between 600 mLH₂O and 600 mL acetone. 750 mL sat. NaHCO_(3 (aq)), was added over 30min. The resulting precipitate was isolated via filtration and rinsedwith 300 mL H₂O then 300 mL acetone. The precipitate was triturated with1.5 L acetone at 50° Celsius for 16 hours. After cooling to roomtemperature the solid was collected by filtration and rinsed twice with250 mL acetone then dried in a vacuum oven at 50° Celsius for 16 hoursyielding the title compound (74.3 g, 72.4%). MS (ESI): mass calcd. forC₁₆H₁₃FN₄O₂S, 344.07; m/z found, 345.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.44-8.36 (s, 1H), 8.10-8.02 (m, 2H), 7.92-7.85 (m, 1H), 7.69-7.59 (m,2H), 7.43-7.35 (m, 3H), 7.35-7.27 (m, 2H), 6.77-6.69 (s, 2H). Elementalanalysis: calcd. for C₁₆H₁₃FN₄O₂S, C, 55.80; H, 3.81; N, 16.27;measured: C, 55.43; H, 3.54; N, 16.22.

Example 6

4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-sulfonamide

To a 5 mL microwave vial were added a stirbar,5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(54 mg, 0.17 mmol), 2-bromo-N-cyclohexylbenzenesulfonamide (58 mg, 0.18mmol), Pd(dppf)Cl₂.CH₂Cl₂ (10 mg, 0.013 mmol), and K₂CO₃ (80 mg, 0.58mmol). The vial was capped and flushed with nitrogen before adding 1 mLN₂ sparged DMSO and heating at 80° Celsius for 20 hours. The vial wascooled to rt and the reaction mixture subjected to FCC purification togive the title compound (45 mg, 62%). MS (ESI): mass calcd. forC₂₂H₂₃FN₄O₂S, 426.15; m/z found, 427.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.43-8.35 (m, 1H), 8.05-8.03 (d, J=1.4, 1H), 8.03-7.99 (dd, J=7.9,1.4, 1H), 7.92-7.84 (m, 1H), 7.70-7.64 (m, 1H), 7.64-7.58 (m, 1H),7.44-7.37 (m, 2H), 7.32-7.24 (m, 2H), 6.72 (s, 2H), 2.85-2.72 (m, 1H),1.69-1.52 (m, 5H), 1.48-1.39 (m, 1H), 1.19-0.93 (m, 5H).

Example 7

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(2-methylpropyl)benzenesulfonamide. MS (ESI): mass calcd. forC₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.42-8.37 (m, 1H), 8.05-8.01 (d, J=1.5, 1H), 7.95-7.91 (dd, J=7.9,1.3, 1H), 7.91-7.86 (m, 1H), 7.70-7.65 (m, 1H), 7.64-7.59 (m, 1H),7.55-7.49 (m, 1H), 7.44-7.40 (dd, J=7.5, 1.4, 1H), 7.33-7.26 (m, 2H),6.73 (s, 2H), 2.55-2.51 (m, 2H), 1.65-1.54 (m, 1H), 0.81-0.75 (d, J=6.7,6H).

Example 8

racemic4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing racemic2-bromo-N-(2,2,2-trifluoro-1-methylethyl)-benzene-sulfonamide. MS (ESI):mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.54-8.47 (d, J=8.9, 1H), 8.43-8.36 (m, 1H),8.09-8.00 (m, 2H), 7.93-7.86 (m, 1H), 7.73-7.68 (m, 1H), 7.68-7.61 (m,1H), 7.44-7.39 (dd, J=7.5, 1.4, 1H), 7.30-7.21 (m, 2H), 6.73 (s, 2H),3.96-3.83 (m, 1H), 1.19-1.10 (d, J=6.9, 3H).

Example 9

4′-(5-Aminopyrazin-2-yl)-N-(cyclobutylmethyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(cyclobutylmethyl)benzenesulfonamide. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.41-8.36 (dd, J=2.2, 1.4, 1H), 8.06-8.01 (d, J=1.5, 1H),7.97-7.91 (dd, J=7.9, 1.4, 1H), 7.91-7.85 (m, 1H), 7.71-7.65 (m, 1H),7.65-7.59 (m, 1H), 7.52-7.47 (m, 1H), 7.44-7.39 (dd, J=7.5, 1.4, 1H),7.33-7.24 (m, 2H), 6.73 (s, 2H), 2.79-2.69 (dd, J=7.2, 5.8, 2H),2.35-2.24 (m, 1H), 1.93-1.82 (m, 2H), 1.81-1.67 (m, 2H), 1.59-1.50 (m,2H).

Example 10

racemic(endo)-4′-(5-Aminopyrazin-2-yl)-N-bicyclo[2.2.1]hept-2-yl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing racemic(endo)-N-Bicyclo[2.2.1]hept-2-yl-2-bromobenzenesulfonamide. MS (ESI):mass calcd. for C₂₃H₂₃FN₄O₂S, 438.15; m/z found, 439.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.42-8.36 (m, 1H), 8.06-8.01 (d, J=1.5, 1H),7.99-7.94 (dd, J=7.9, 1.3, 1H), 7.91-7.85 (m, 1H), 7.71-7.65 (m, 1H),7.65-7.60 (m, 1H), 7.43-7.39 (dd, J=7.5, 1.4, 1H), 7.39-7.34 (d, J=6.9,1H), 7.30-7.22 (m, 2H), 6.73 (s, 2H), 2.83-2.74 (m, 1H), 2.12-2.06 (m,1H), 1.97-1.92 (m, 1H), 1.47-1.37 (m, 2H), 1.34-1.21 (m, 3H), 1.01-0.77(m, 4H).

Example 11

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methylcyclobutyl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(1-methylcyclobutyl)benzenesulfonamide. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.1 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃) δ 8.52 (s, 1H), 8.26 (s, 1H), 8.16-8.11 (dd, J=7.9, 1.3, 1H),8.11-8.05 (m, 1H), 7.62-7.58 (m, 1H), 7.56-7.51 (m, 1H), 7.40-7.37 (dd,J=8.1, 1.7, 1H), 7.34-7.28 (m, 2H), 4.37 (s, 1H), 2.13-2.00 (m, 2H),1.82-1.73 (m, 2H), 1.69-1.59 (m, 2H), 1.24 (s, 3H).

Example 12

4′-(5-Aminopyrazin-2-yl)-N-(1,1-dimethylpropyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(1,1-dimethylpropyl)benzenesulfonamide. MS (ESI): mass calcd.for C₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.1 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃) δ 8.56 (s, 1H), 8.28 (s, 1H), 8.18-8.13 (dd, J=7.9, 1.3, 1H),8.12-8.06 (m, 1H), 7.62-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.44-7.39 (dd,J=8.1, 1.7, 1H), 7.35-7.28 (m, 2H), 3.90 (s, 1H), 1.50-1.39 (q, J=7.4,2H), 1.01 (s, 6H), 0.78-0.68 (t, J=7.4, 3H).

Example 13

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(2,2,2-trifluoro-1,1-dimethylethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₁₈F₄N₄O₂S, 454.11; m/z found, 455.1 [M+H]⁺.¹H NMR (600 MHz, CDCl₃) δ 8.54 (s, 1H), 8.27 (s, 1H), 8.15-8.10 (dd,J=8.0, 1.3, 1H), 8.10-8.04 (m, 1H), 7.66-7.59 (m, 1H), 7.57-7.52 (m,1H), 7.40-7.27 (m, 3H), 4.49 (s, 1H), 1.33 (s, 6H).

Example 14

4′-(5-Aminopyrazin-2-yl)-N-cyclopentyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-cyclopentylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ8.46 (s, 1H), 8.21 (s, 1H), 8.14-8.10 (dd, J=8.0, 1.4, 1H), 8.10-8.04(m, 1H), 7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.38-7.25 (m, 3H),4.42-4.25 (d, J=6.6, 1H), 3.49-3.35 (m, 1H), 1.80-1.66 (m, 2H),1.63-1.48 (m, 2H), 1.48-1.38 (m, 2H), 1.35-1.19 (m, 2H).

Example 15

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 2-bromo-N-methylbenzenesulfonamide. MS(ESI): mass calcd. for C₁₇H₁₅FN₄O₂S, 358.09; m/z found, 359.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.32 (s, 2H), 8.07-8.01 (dd, J=7.9, 1.4, 1H),7.99-7.94 (m, 1H), 7.71-7.64 (m, 1H), 7.63-7.57 (m, 1H), 7.43-7.37 (dd,J=7.5, 1.4, 1H), 7.35-7.26 (m, 2H), 2.45 (s, 3H).

Example 16

4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 2-bromo-N-ethylbenzenesulfonamide. MS(ESI): mass calcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.37 (s, 1H), 8.30 (s, 1H), 8.10-8.01 (dd, J=8.0,1.5, 1H), 8.01-7.93 (m, 1H), 7.70-7.62 (m, 1H), 7.62-7.54 (m, 1H),7.42-7.36 (dd, J=7.6, 1.5, 1H), 7.35-7.25 (m, 2H), 2.91-2.74 (q, J=7.2,2H), 1.08-0.93 (t, J=7.2, 3H).

Example 17

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-phenylethyl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(2-phenylethyl)benzenesulfonamide. MS (ESI): mass calcd. forC₂₄H₂₁FN₄O₂S, 448.14; m/z found, 449.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.35 (s, 1H), 8.14 (s, 1H), 8.10-8.05 (dd, J=7.9, 1.3, 1H), 7.99-7.91(m, 1H), 7.63-7.57 (m, 1H), 7.57-7.49 (m, 1H), 7.31-7.26 (dd, J=7.5,1.4, 1H), 7.23-7.17 (m, 2H), 7.17-7.09 (m, 3H), 7.05-6.98 (m, 2H),4.82-4.67 (m, 1H), 3.15-3.00 (m, 2H), 2.75-2.65 (t, J=7.1, 2H).

Example 18

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-benzene-sulfonamide. MS(ESI): mass calcd. for C₂₄H₁₈F₄N₄O₂S, 502.08; m/z found, 503.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.37-8.31 (s, 1H), 8.23-8.18 (dd, J=8.0, 1.4,1H), 7.99-7.93 (d, J=1.6, 1H), 7.87-7.80 (m, 1H), 7.63-7.57 (m, 1H),7.55-7.49 (m, 1H), 7.36-7.31 (d, J=7.4, 1H), 7.30-7.25 (m, 2H),7.23-7.18 (d, J=7.6, 1H), 7.20-7.10 (m, 2H), 7.11-7.02 (m, 2H),5.04-4.93 (s, 2H), 4.84-4.72 (m, 1H).

Example 19

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]-benzene-sulfonamide.

Example 20

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzene-sulfonamide. MS(ESI): mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.21-8.12 (m, 2H), 7.92-7.85 (s, 1H),7.85-7.79 (m, 1H), 7.62-7.55 (m, 1H), 7.54-7.47 (m, 1H), 7.43-7.36 (d,J=8.0, 1H), 7.33-7.27 (dd, J=7.5, 1.4, 1H), 7.19-7.07 (d, J=12.6, 1H),5.45-5.13 (s, 2H), 4.04-3.90 (m, 1H), 1.31-1.22 (d, J=7.0, 3H).

Example 21

4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-(2,3-dihydro-1H-inden-2-yl)benzenesulfonamide. MS (ESI): masscalcd. for C₂₅H₂₁FN₄O₂S, 460.14; m/z found, 461.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.44-8.39 (m, 1H), 8.24-8.18 (dd, J=8.0, 1.4, 1H),8.05-8.00 (d, J=1.5, 1H), 7.91-7.84 (m, 1H), 7.65-7.58 (m, 1H),7.58-7.51 (m, 1H), 7.34-7.29 (dd, J=7.5, 1.4, 1H), 7.27-7.21 (m, 1H),7.15-7.04 (m, 5H), 4.89-4.74 (s, 2H), 4.74-4.61 (d, J=6.6, 1H),4.00-3.89 (m, 1H), 3.06-2.92 (dd, J=15.9, 6.9, 2H), 2.70-2.58 (dd,J=15.9, 5.6, 2H).

Example 22

(S)-4′-(5-Aminopyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide. MS (ESI):mass calcd. for C₂₅H₂₁FN₄O₂S, 460.14; m/z found, 461.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.30-8.24 (dd, J=7.9, 1.4, 1H), 8.24-8.19 (m, 1H),8.00-7.95 (d, J=1.5, 1H), 7.85-7.78 (m, 1H), 7.65-7.58 (m, 1H),7.58-7.52 (m, 1H), 7.34-7.27 (dd, J=7.5, 1.4, 1H), 7.23-7.18 (d, J=7.7,1H), 7.18-7.12 (dd, J=4.9, 1.1, 2H), 7.07-6.98 (m, 2H), 6.96-6.88 (d,J=7.6, 1H), 5.05-4.90 (d, J=8.7, 1H), 4.87-4.79 (s, 2H), 4.79-4.71 (m,1H), 2.86-2.74 (m, 1H), 2.74-2.60 (m, 1H), 2.28-2.16 (m, 1H), 1.79-1.64(m, 1H).

Example 23

(R)-4′-(5-Aminopyrazin-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1R)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide.

Example 24

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 using2-bromo-N-[(1R)-1-phenylethyl]benzenesulfonamide. MS (ESI): mass calcd.for C₂₄H₂₁FN₄O₂S, 448.14; m/z found, 449.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.44-8.37 (d, J=1.4, 1H), 8.19-8.12 (m, 1H), 8.10-8.03 (dd,J=8.0, 1.3, 1H), 7.97-7.89 (m, 1H), 7.61-7.53 (m, 1H), 7.52-7.45 (m,1H), 7.22-7.15 (m, 4H), 7.12-7.00 (s, 1H), 6.97-6.91 (m, 2H), 6.89-6.78(s, 1H), 4.68-4.51 (d, J=7.0, 1H), 4.39-4.25 (m, 1H), 1.45-1.33 (d,J=6.9, 3H).

Example 25

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.38-8.28 (m, 2H), 8.16-8.11 (dd, J=8.0, 1.3, 1H),8.01-7.93 (m, 1H), 7.71-7.63 (m, 1H), 7.62-7.55 (m, 1H), 7.43-7.37 (dd,J=7.6, 1.4, 1H), 7.37-7.30 (m, 2H), 3.42-3.37 (m, 1H), 3.30-3.25 (dd,J=10.9, 6.3, 1H), 3.24-3.16 (m, 1H), 1.04-0.98 (d, J=6.6, 3H).

Example 26

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 2-bromo-N-phenylbenzenesulfonamide. MS(ESI): mass calcd. for C₂₂H₁₇FN₄O₂S, 420.11; m/z found, 421.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.45-8.37 (m, 1H), 8.13-8.06 (d,J=1.5, 1H), 8.06-8.00 (dd, J=8.0, 1.4, 1H), 7.92-7.84 (t, J=8.3, 1H),7.70-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.39-7.32 (dd, J=7.6, 1.4, 1H),7.24-7.16 (dd, J=8.5, 7.3, 2H), 7.12 (s, 1H), 7.11-7.08 (dd, J=4.1, 1.6,1H), 7.01-6.96 (m, 1H), 6.95-6.89 (m, 2H).

Example 27

(S)-4′-(5-Aminopyrazin-2-yl)-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]benzenesulfonamide. MS (ESI):mass calcd. for C₂₄H₂₆FN₅O₃S, 483.17; m/z found, 484.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.39-8.33 (d, J=1.4, 1H), 8.25-8.20 (d, J=1.4, 1H),8.10-8.05 (m, 1H), 8.05-8.00 (dd, J=8.0, 1.3, 1H), 7.61-7.55 (m, 1H),7.53-7.47 (m, 1H), 7.43-7.38 (dd, J=8.1, 1.7, 1H), 7.34-7.30 (dd, J=7.5,1.4, 1H), 7.30-7.25 (dd, J=12.3, 1.7, 1H), 6.02-5.93 (d, J=5.5, 1H),3.91-3.83 (m, 1H), 3.45-3.20 (m, 3H), 3.18-3.10 (m, 1H), 2.04-1.94 (m,1H), 1.92-1.81 (m, 1H), 1.81-1.70 (m, 1H), 1.66-1.53 (m, 1H), 1.52-1.42(m, 1H), 1.34-1.21 (m, 1H), 1.09-0.99 (t, J=7.2, 3H).

Example 28

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-2-oxoazepan-3-yl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(3S)-2-oxoazepan-3-yl]benzenesulfonamide. MS (ESI): masscalcd. for C₂₂H₂₂FN₅O₃S, 455.14; m/z found, 456.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.46-8.33 (s, 1H), 8.24-8.14 (s, 1H), 8.10-8.00 (m, 2H),7.63-7.56 (m, 1H), 7.56-7.48 (m, 1H), 7.41-7.35 (dd, J=8.0, 1.7, 1H),7.35-7.29 (dd, J=7.4, 1.4, 1H), 7.29-7.25 (d, J=1.8, 1H), 7.00-6.82 (s,1H), 5.88-5.71 (d, J=6.0, 1H), 3.89-3.73 (d, J=9.4, 1H), 3.24-3.11 (m,1H), 3.11-2.97 (m, 1H), 2.09-1.98 (d, J=12.5, 1H), 1.98-1.85 (d, J=13.2,1H), 1.81-1.67 (m, 1H), 1.64-1.44 (m, 2H), 1.37-1.21 (m, 1H).

Example 29

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-1-methyl-2-oxoazepan-3-yl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(3S)-1-methyl-2-oxoazepan-3-yl]benzenesulfonamide. MS (ESI):mass calcd. for C₂₃H₂₄FN₅O₃S, 469.16; m/z found, 470.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.44-8.38 (d, J=1.3, 1H), 8.22 (s, 1H), 8.10-8.05 (m,1H), 8.05-8.00 (dd, J=7.9, 1.3, 1H), 7.63-7.56 (m, 1H), 7.54-7.47 (m,1H), 7.43-7.37 (dd, J=8.1, 1.5, 1H), 7.34-7.29 (dd, J=7.6, 1.4, 1H),7.28-7.24 (m, 1H), 6.00-5.85 (d, J=5.6, 1H), 3.98-3.86 (d, J=11.4, 1H),3.39-3.28 (dd, J=15.2, 11.4, 1H), 3.16-3.05 (dd, J=15.3, 5.1, 1H), 2.95(s, 3H), 2.04-1.93 (dd, J=17.1, 4.1, 1H), 1.91-1.81 (m, 1H), 1.77-1.66(m, 1H), 1.65-1.53 (m, 1H), 1.53-1.42 (m, 1H), 1.38-1.26 (m, 1H).

Example 30

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example Example 6 utilizing2-bromo-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₆H₃₂FN₅O₂S, 497.23; m/z found, 498.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.39-8.35 (d, J=1.4, 1H), 8.35-8.30 (m, 1H),8.18-8.13 (dd, J=8.0, 1.3, 1H), 8.05-7.99 (m, 1H), 7.73-7.67 (m, 1H),7.65-7.59 (m, 1H), 7.45-7.40 (dd, J=7.6, 1.3, 1H), 7.39-7.36 (m, 1H),7.36-7.32 (dd, J=102.9, 1.5, 1H), 3.49-3.39 (m, 1H), 2.75 (s, 3H),1.95-1.87 (m, 2H), 1.75-1.64 (m, 2H), 1.38 (s, 6H), 1.30 (s, 6H).

Example 31

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-pyridin-3-ylbiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-pyridin-3-ylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₁H₁₆FN₅O₂S, 421.10; m/z found, 422.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.38-8.34 (d, J=1.5, 1H), 8.34-8.30 (m, 2H), 8.29-8.23 (m, 2H),7.91-7.85 (m, 1H), 7.83-7.79 (m, 1H), 7.75-7.71 (m, 1H), 7.71-7.68 (dd,J=8.6, 5.4, 1H), 7.68-7.64 (m, 1H), 7.41-7.37 (dd, J=7.6, 1.3, 1H),7.20-7.15 (dd, J=12.1, 1.7, 1H), 7.15-7.12 (dd, J=8.0, 1.7, 1H).

Example 32

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-N-[(1S)-2-hydroxy-1-methylethyl]benzenesulfonamide.

Example 33

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfamide

To a solution of tert-butanol (13 mg, 0.18 mmol) in DCM (5 mL) was addedchlorosulfonylisocyanate (25 mg, 0.18 mmol) at 0° Celsius. The resultingsolution containing N-(tert-butoxycarbonyl)sulfamoyl chloride was addedto a reaction flask containing5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine (50 mg, 0.18 mmol) andtriethylamine (36 mg, 0.36 mmol) in anhydrous DCM (10 mL) at 0° Celsius.The mixture was warmed to rt, stirred 2 hours, then concentrated todryness, re-dissolved in TFA/DCM (5 mL/5 mL), stirred at rt for 1 hour,and concentrated to dryness. The residue was diluted with water (10 mL)and saturated NaHCO_(3(aq)) (10 mL), extracted with DCM (10 mL×3) andthe combined organic extracts washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by HPLCto give the title compound (10 mg, 16%). MS (ESI): mass calcd. forC₁₆H₁₄FN₅O₂S, 359.09; m/z found, 360.0 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆)δ 8.39 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=1.3, 1H), 7.91 (m, 1H), 7.63(d, J=7.8, 1H), 7.44-7.22 (m, 4H), 7.24 (m, 1H), 7.05 (s, 2H), 6.70 (s,2H).

Example 34

N-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)propane-2-sulfonamide

To a solution of 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (309 mg, 1.15mmol) in DMSO (5 mL) was added K₂CO₃ (317 mg, 2.3 mmol). The mixture wassparged with N₂ several times. Pd(PPh₃)₄ (66 mg, 0.058 mmol) and(2-(1-methylethylsulfonamido)-phenyl)boronic acid (280 mg, 1.15 mmol)were added and the resultant mixture sparged with N₂. The mixture washeated at 80° Celsius for 14 hours before cooling to rt and dilutingwith water (70 mL). The precipitate was collected, rinsed with water,air dried, and then purified by HPLC to give the title compound (40 mg,9%). MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.1[M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.72 (s, 1H), 8.25 (d, J=1.2, 1H),8.16 (m, 1H), 7.50 (d, J=7.8, 1H), 7.47-7.34 (m, 5H), 3.15-3.03 (m, 1H),1.23 (d, J=6.8, 6H).

Example 35

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 34 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand N-(2-bromophenyl)ethanesulfonamide. MS (ESI): mass calcd. forC₁₈H₁₇FN₄O₂S, 372.11; m/z found, 372.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.08 (s, 1H), 8.43-8.36 (m, 1H), 8.04 (d, J=1.0, 1H), 7.93 (m, 1H),7.46-7.28 (m, 6H), 6.72 (s, 2H), 2.91 (q, J=7.4, 2H), 1.07 (t, J=7.3,3H).

Example 36

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]propane-1-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 34 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-bromo-2-(propylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.09 (s, 1H), 8.38 (s, 1H), 8.04 (d, J=1.3, 1H), 7.93 (m, 1H),7.42-7.35 (m, 6H), 6.71 (s, 2H), 2.87-2.74 (m, 2H), 1.59-1.44 (m, 2H),0.81 (t, J=7.4, 3H).

Example 37

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-2-methylpropane-1-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 34 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand N-(2-bromophenyl)isobutylsulfonamide. MS (ESI): mass calcd. forC₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.38 (s, 1H), 8.14 (s, 1H), 7.96 (m, 1H), 7.49 (d, J=7.0, 1H), 7.45-7.30(m, 5H), 2.77 (d, J=6.5, 2H), 2.15-2.02 (m, 1H), 0.97 (d, J=6.7, 6H).

Example 38

N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropanesulfonamideStep A:2-(di-tert-Butyloxycarbonyl)amino-5-(4-bromo-2-fluorophenyl)pyrazine

2-Amino-5-(4-bromo-2-fluorophenyl)pyrazine (3.0 g, 11 mmol) wasdissolved in pyridine (40 mL), and then slowly treated with (Boc)₂O (6.8g, 34 mmol) at rt. The mixture was stirred at rt for 18 hours,concentrated to dryness and purified by FCC to give2-(di-tert-butyloxycarbonyl)amino-5-(4-bromo-2-fluorophenyl)pyrazine(3.6 g, 68%) as a white solid. MS (ESI): mass calcd. for C₂₀H₂₃FBrN₃O₄S,467.09; m/z found, 468.0 [M+H]⁺.

Step B:2-(di-tert-Butyloxycarbonyl)amino-5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazine

To a solution of2-(di-tert-butyloxycarbonyl)amino-5-(4-bromo-2-fluorophenyl)-pyrazine(232 mg, 0.5 mmol) and 2-aminophenylboronic acid hydrochloride (174 mg,1.0 mmol) in 1,4-dioxane/H₂O (10 mL/0.5 mL) was added Na₂CO₃ (232 mg,2.0 mmol). The mixture was sparged with N₂ several times. Pd(PPh₃)₄ (29mg, 0.025 mmol) was added and the resulted mixture was stirred at 80°Celsius for 14 hours under N₂. After cooling to rt, the mixture wasdiluted with water (50 mL) and extracted with DCM (15 mL×3). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness to give2-(di-tert-butyloxycarbonyl)amino-5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazine,which was directly used in next step without any further purification.MS (ESI): mass calcd. for C₂₆H₂₉FN₄O₄S, 480.22; m/z found, 481.0 [M+H]⁺.

Step C

To a solution of2-(di-tert-butyloxycarbonyl)amino-5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazine(280 mg crude, 0.5 mmol) in pyridine (5 mL) was slowly addedcyclopropane-sulfonyl chloride (105 mg, 0.75 mmol) at rt. The resultantmixture was stirred at 60° Celsius for 16 hours. The mixture wasconcentrated to dryness, the residue diluted with 40 mL of water andextracted with DCM (10 mL×2). The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by FCC to give 230 mg of impure product. The solidwas dissolved in HCl (4 N) in EtOH (5 mL) and stirred at rt for 1 hour,then concentrated to dryness. The residue was purified by HPLC to givethe title compound (55 mg, 37% yield). MS (ESI): mass calcd. forC₁₉H₁₇FN₄O₄S, 384.11; m/z found, 385.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 9.14 (s, 1H), 8.39 (s, 1H), 8.05 (d, J=1.3, 1H), 7.92 (m, 1H), 7.51(d, J=7.8, 1H), 7.48-7.34 (m, 5H), 6.81 (s, 2H), 2.48-2.42 (m, 1H),0.89-0.75 (m, 4H).

Example 39

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]hexane-1-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 38 utilizing hexane-1-sulfonyl chloride. MS (ESI):mass calcd. for C₂₂H₂₅FN₄O₂S, 428.17; m/z found, 429.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.40 (s, 1H), 8.04 (d, J=1.1, 1H),7.96 (m, 1H), 7.48-7.34 (m, 6H), 6.73 (s, 2H), 2.77-2.63 (m, 2H),1.41-1.33 (m, 2H), 1.16-0.95 (m, 6H), 0.72 (t, J=6.9, 3H).

Example 40

N-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclobutanesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 38 utilizing cyclobutanesulfonyl chloride. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.0 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.92(m, 1H), 7.47-7.31 (m, 6H), 6.71 (s, 2H), 3.66 (p, J=7.7, 1H), 2.21-2.08(m, 2H), 2.03-1.92 (m, 2H), 1.86-1.70 (m, 2H).

Example 41

[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide

Trifluoromethanesulfonic anhydride (263 mg, 0.95 mmol) was addeddrop-wise to a solution consisting of2-(di-tert-butyloxycarbonyl)amino-5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazine(300 mg, 0.62 mmol) and Et₃N (190 mg, 1.86 mmol) and DCM (10 mL), at rt.The resulting mixture was stirred at rt for 16 hours, then quenched withsat. NaHCO₃ (20 mL), diluted with water (40 mL), and extracted with DCM(15 mL×3). The combined organic fractions were washed with brine, driedover Na₂SO₄ and concentrated to dryness. The solid was dissolved in 4 NHCl in EtOH (10 mL) and stirred at rt for 1 hour, concentrated todryness and purified by HPLC to give the title compound. MS (ESI): masscalcd. for C₁₇H₁₂F₄N₄O₂S, 412.06; m/z found, 413.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.06 (s, 1H), 7.96 (m, 1H), 7.56-7.45 (m,3H), 7.44-7.32 (m, 3H), 6.77 (s, 2H).

Example 42

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide

To a 20 mL vial were 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (50 mg,0.19 mmol), (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid, K₂CO₃ (43 mg,0.19 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (8 mg, 0.009 mmol), and a stir-bar.The vial was sealed with a teflon lined cap and sparged with N₂. Thevial was then charged with freshly sparged DMSO (2 mL) and then stirred16 hours at 80° Celsius. The reaction mixture was then cooled to rt,filtered, and purified by HPLC to give the title compound (36 mg, 40%).MS (ESI): mass calcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 2H), 8.06-7.96 (m, 2H), 7.72-7.67 (m,1H), 7.64-7.59 (m, 1H), 7.43-7.39 (m, 1H), 7.32-7.26 (m, 2H), 2.49 (s,6H).

Example 43

5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 42 using 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and(2-(piperidin-1-ylsulfonyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.40-8.30 (m, 2H), 8.10-8.06 (m, 1H), 7.98 (m, 1H), 7.79-7.73(m, 1H), 7.71-7.64 (m, 1H), 7.62-7.56 (m, 1H), 7.43-7.39 (m, 1H),7.34-7.28 (m, 1H), 2.86 (d, J=5.3, 4H), 1.50-1.38 (m, 6H).

Example 44

5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 42 using 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and(2-(morpholinosulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.38 (s, 1H), 8.31 (s, 1H), 8.13-8.09 (m, 1H), 7.99 (m, 1H), 7.75-7.69(m, 1H), 7.65-7.60 (m, 1H), 7.46-7.43 (m, 1H), 7.37-7.31 (m, 2H),3.54-3.46 (m, 4H), 2.91-2.84 (m, 4H).

Example 45

5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₄S₂, 462.08; m/z found, 463.0 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.62-8.60 (m, 1H), 8.16-8.14 (m, 1H), 8.13-8.12 (m,1H), 8.05 (t, J=8.1 Hz, 1H), 7.69-7.65 (m, 1H), 7.59-7.54 (m, 1H),7.39-7.36 (m, 1H), 7.25-7.21 (m, 2H), 4.81 (s, 2H), 3.36-3.30 (m, 4H),3.02-2.98 (m, 4H).

Example 46

5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)piperazine. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.39 (m, 1H), 8.21-8.13 (m, 2H), 8.01-7.95 (m, 1H), 7.79-7.74 (m, 1H),7.69-7.63 (m, 1H), 7.50-7.46 (m, 1H), 7.37-7.30 (m, 2H), 3.14-3.08 (m,4H), 3.06-2.99 (m, 4H).

Example 47

4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.37 (s, 1H), 8.29 (d, J=1.4, 1H), 8.08-8.04 (m, 1H), 8.0-7.94 (m, 1H),7.70-7.64 (m, 1H), 7.61-7.55 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.25 (m,2H), 2.96 (q, J=7.1, 4H), 1.00 (t, J=7.1, 6H).

Example 48

5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)pyrrolidine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.38 (s, 1H), 8.28 (d, J=1.4, 1H), 8.12-8.08 (m, 1H), 8.0-7.94 (m, 1H),7.71-7.65 (m, 2H), 7.62-7.56 (m, 1H), 7.42-7.39 (m, 1H), 7.34-7.27 (m,2H), 2.94 (t, J=6.7, 4H), 1.81-1.69 (m, 4H).

Example 49

5-{2′-[(4,4-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-4,4-difluoropiperidine. MS (ESI): masscalcd. for C₂₁H₁₉F₃N₄O₂S, 448.12; m/z found, 449.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.35 (s, 1H), 8.27 (d, J=1.4, 1H), 8.12 (d, J=8.0, 1H),7.98 (m, 1H), 7.75-7.67 (m, 1H), 7.63 (m, 1H), 7.43 (d, J=7.6, 1H), 7.32(d, J=10.6, 2H), 3.02-2.93 (m, 4H), 1.90-1.73 (m, 4H).

Example 50

5-{2′-[(3,3-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-difluoropiperidine. MS (ESI): masscalcd. for C₂₁H₁₉F₃N₄O₂S, 448.12; m/z found, 449.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.35-8.27 (m, 2H), 8.12-8.05 (m, 1H), 8.01-7.94 (m, 1H),7.74-7.67 (m, 1H), 7.65-7.58 (m, 1H), 7.44-7.38 (m, 1H), 7.32-7.24 (m,2H), 3.04-2.96 (m, 2H), 2.95-2.88 (m, 2H), 1.96-1.82 (m, 2H), 1.69-1.61(m, 2H).

Example 51

5-{2′-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-difluoropyrrolidine. MS (ESI): masscalcd. for C₂₀H₁₇F₃N₄O₂S, 434.10; m/z found, 435.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.35 (d, J=1.3, 1H), 8.27 (d, J=1.4, 1H), 8.11 (d, J=7.9,1H), 7.99 (m, 1H), 7.77-7.69 (m, 1H), 7.67-7.59 (m, 1H), 7.47-7.40 (m,1H), 7.34-7.25 (m, 2H), 3.23 (t, J=12.9, 2H), 3.14 (t, J=7.3, 2H),2.28-2.14 (m, 2H).

Example 52

5-{2′-[(3,3-Difluoroazetidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-difluoroazetidine. MS (ESI): masscalcd. for C₁₉H₁₅F₃N₄O₂S, 420.09; m/z found, 421.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.37-8.26 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.95 (m, 1H),7.77-7.69 (m, 1H), 7.66-7.57 (m, 1H), 7.48-7.40 (m, 1H), 7.35-7.24 (m,2H), 4.02-3.92 (m, 4H).

Example 53

5-[2′-(Azepan-1-ylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)azepane. MS (ESI): mass calcd. forC₂₂H₂₃FN₄O₂S, 426.15; m/z found, 427.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.37 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9, 1H), 7.96 (t, J=8.2, 1H),7.66 (m, 1H), 7.60-7.55 (m, 1H), 7.38 (d, J=6.5, 1H), 7.31-7.24 (m, 2H),1.63-1.52 (m, 12H).

Example 54

5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-4-methylpiperazine. MS (ESI): masscalcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.37 (m, 1H), 8.23 (d, J=1.4, 1H), 8.16-8.12 (m, 1H),8.02-7.96 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.62 (m, 1H), 7.48-7.45 (m,1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.61-3.33 (m, 4H), 3.01-2.70 (m,7H).

Example 55

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(trifluoromethyl)piperidin-4-ol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-4-(trifluoromethyl)piperidin-4-ol. MS(ESI): mass calcd. for C₂₂H₂₀F₄N₄O₃S, 496.12; m/z found, 497.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.23 (d, J=1.1, 1H), 8.15-8.11(m, 1H), 7.94 (m, 1H), 7.75-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.41(m, 1H), 7.35-7.27 (m, 2H), 3.29-3.22 (m, 2H), 2.79-2.64 (m, 2H),1.65-1.48 (m, 4H).

Example 56

5-(3-Fluoro-2′-{[4-(methylsulfonyl)piperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-4-(methylsulfonyl)piperazine. MS (ESI):mass calcd. for C₂₁H₂₂FN₅O₄S₂, 491.11; m/z found, 492.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.23 (s, 1H), 8.13 (d, J=7.0, 1H), 7.97(m, 1H), 7.77-7.71 (m, 1H), 7.67-7.61 (m, 1H), 7.46 (d, J=6.4, 1H),7.39-7.32 (m, 2H), 3.03-2.94 (m, 8H), 2.78 (s, 3H).

Example 57

5-{2′-[(4-Acetylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanone. MS (ESI):mass calcd. for C₂₂H₂₂FN₅O₃S, 455.14; m/z found, 456.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.34 (d, J=6.0, 2H), 8.11-8.08 (m, 1H), 8.00 (m, 1H),7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.37-7.29 (m,2H), 3.43-3.34 (m, 4H), 2.96-2.81 (m, 4H), 2.02 (s, 3H).

Example 58

5-(2′-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (4-((2-bromophenyl)sulfonyl)piperazin-1-yl)(cyclopropyl)-methanone.MS (ESI): mass calcd. for C₂₄H₂₄FN₅O₃S, 481.16; m/z found, 482.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.63-8.59 (m, 1H), 8.16-8.10 (m, 2H), 8.00 (m,1H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.36 (m, 1H), 7.32-7.30(m, 1H), 7.28 (s, 1H), 4.76 (s, 2H), 3.48 (s, 4H), 2.94-2.82 (m, 4H),1.63-1.54 (m, 1H), 0.97-0.89 (m, 2H), 0.79-0.70 (m, 2H).

Example 59

2-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanol. MS (ESI): masscalcd. for C₂₂H₂₄FN₅O₃S, 457.16; m/z found, 458.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.38 (m, 1H), 8.21 (d, J=1.5, 1H), 8.16-8.13 (m, 1H), 7.98(m, 1H), 7.79-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.45 (m, 1H),7.36-7.30 (m, 2H), 3.86-3.78 (m, 2H), 3.66-3.32 (m, 4H), 3.24-3.20 (m,2H), 3.15-2.72 (m, 4H).

Example 60

5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-4-cyclopropylpiperazine. MS (ESI): masscalcd. for C₂₃H₂₄FN₅O₂S, 453.16; m/z found, 454.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.40 (s, 1H), 8.18-8.12 (m, 2H), 7.97 (m, 1H), 7.79-7.74(m, 1H), 7.68-7.63 (m, 1H), 7.49-7.46 (m, 1H), 7.34-7.30 (m, 2H),3.28-2.98 (d, J=1.6, 8H), 2.82-2.75 (m, 1H), 0.96-0.85 (m, 4H).

Example 61

racemic5-[3-Fluoro-2′-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic 2-((2-bromophenyl)sulfonyl)octahydropyrrolo[1,2-a]pyrazine.MS (ESI): mass calcd. for C₂₃H₂₄FN₅O₂S, 453.16; m/z found, 454.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=1.4, 1H), 8.24 (d, J=1.4, 1H),8.17-8.13 (m, 1H), 7.99 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.63 (m, 1H),7.48-7.45 (m, 1H), 7.36-7.30 (m, 2H), 3.89-3.35 (m, 4H), 3.26-2.53 (m,6H), 2.18-1.97 (m, 3H).

Example 62

Racemic-5-{2′-[(3,5-Dimethylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand Racemic-1-((2-bromophenyl)sulfonyl)-3,5-dimethylpiperazine. MS(ESI): mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.24 (d, J=1.4, 1H), 8.17-8.14 (m,1H), 7.99 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.46 (m,1H), 7.37-7.32 (m, 2H), 3.49-3.42 (m, 2H), 3.14-3.01 (m, 2H), 2.47-2.39(m, 2H), 1.17 (d, J=6.6, 6H).

Example 63

racemic1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-3-carbonitrile

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic 1-((2-bromophenyl)sulfonyl)piperidine-3-carbonitrile. MS(ESI): mass calcd. for C₂₂H₂₀FN₅O₂S, 437.13; m/z found, 438.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.11-8.07 (m,1H), 7.98 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.60 (m, 1H), 7.44-7.40 (m,1H), 7.36-7.30 (m, 2H), 3.06-3.02 (m, 2H), 2.90-2.86 (m, 2H), 2.80-2.74(m, 1H), 1.89-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.53-1.42 (m, 1H).

Example 64

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carbonitrile

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)piperidine-4-carbonitrile. MS (ESI): masscalcd. for C₂₂H₂₀FN₅O₂S, 437.13; m/z found, 438.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.35 (s, 1H), 8.29 (d, J=1.1, 1H), 8.12-8.09 (m, 1H), 7.99(m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.42 (m, 1H), 7.34(s, 1H), 7.32-7.30 (m, 1H), 3.10-3.02 (m, 2H), 2.86-2.73 (m, 3H),1.82-1.73 (m, 2H), 1.64-1.53 (m, 2H).

Example 65

5-{2′-[(4-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd.for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.36 (s, 1H), 8.25-8.23 (d, J=1.4, 1H), 8.11-8.08 (m, 1H), 7.96(m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H),7.32-7.29 (m, 1H), 7.28 (s, 1H), 3.47-3.40 (m, 2H), 3.18-3.08 (m, 1H),2.57-2.43 (m, 2H), 1.91-1.84 (m, 2H), 1.51-1.39 (m, 2H).

Example 66

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd.for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.37 (s, 1H), 8.27 (d, J=1.4, 1H), 8.17-8.13 (m, 1H), 7.98 (m,1H), 7.77-7.72 (m, 1H), 7.67-7.62 (m, 1H), 7.47-7.43 (m, 1H), 7.34-7.26(m, 2H), 3.39 (s, 2H), 3.14 (s, 4H).

Example 67

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-ol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)piperidin-4-ol. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.36-8.31 (m, 2H), 8.10-8.06 (m, 1H), 7.99 (m, 1H), 7.73-7.67 (m, 1H),7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.28 (m, 2H), 3.66-3.55 (m,1H), 3.20-3.08 (m, 2H), 2.71-2.61 (m, 2H), 1.72-1.63 (m, 2H), 1.39-1.26(m, 2H).

Example 68

(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)methanol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)methanol. MS (ESI): masscalcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.36-8.29 (m, 2H), 8.11-8.07 (m, 1H), 7.98 (m, 1H),7.74-7.67 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.41 (m, 1H), 7.36-7.29 (m,2H), 3.40-3.32 (m, 4H), 2.46-2.36 (m, 2H), 1.59 (d, J=10.5, 2H),1.48-1.36 (m, 1H), 1.01-0.89 (m, 2H).

Example 69

2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)ethanol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)ethanol. MS (ESI): masscalcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.34 (s, 1H), 8.31 (d, J=1.2, 1H), 8.10-8.07 (m, 1H), 7.98(m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.41 (m, 1H), 7.34(s, 1H), 7.32-7.30 (m, 1H), 3.56-3.48 (m, 2H), 3.32 (d, J=4.5, 2H),2.45-2.36 (m, 2H), 1.61-1.54 (m, 2H), 1.46-1.34 (m, 3H), 1.01-0.87 (m,2H).

Example 70

racemic1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-ol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.34 (s, 1H), 8.31 (d, J=1.4, 1H), 8.11-8.06 (m, 1H),8.01-7.96 (m, 1H), 7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m,1H), 7.34-7.32 (m, 1H), 7.31-7.29 (m, 1H), 3.44-3.35 (m, 1H), 3.27-3.21(m, 1H), 3.15-3.06 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.21 (m, 1H),1.88-1.79 (m, 1H), 1.68-1.59 (m, 1H), 1.41-1.28 (m, 1H), 1.26-1.15 (m,1H).

Example 71

racemic-2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic-2-(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)ethanol. MS(ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.36-8.31 (m, 2H), 8.10-8.05 (m, 1H), 8.01-7.95(m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H),7.36-7.29 (m, 2H), 3.52-3.40 (m, 2H), 3.26-3.16 (m, 2H), 2.48-2.36 (m,1H), 2.14-2.08 (m, 1H), 1.77-1.67 (m, 1H), 1.62-1.53 (m, 1H), 1.49-1.37(m, 1H), 1.36-1.25 (m, 3H), 1.02-0.89 (m, 1H).

Example 72

5-(3-Fluoro-2′-{[4-(methylamino)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-N-methylpiperidin-4-amine. MS (ESI):mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.21 (d, J=1.4, 1H), 8.12-8.09 (m, 1H),7.96 (m, 1H), 7.75-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H),7.32-7.30 (m, 1H), 7.28 (s, 1H), 3.49-3.42 (m, 2H), 3.10-3.01 (m, 1H),2.63 (s, 3H), 2.54-2.42 (m, 2H), 2.00-1.92 (m, 2H), 1.47-1.35 (m, 2H).

Example 73

5-(2′-{[4-(Dimethylamino)piperidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)-N,N-dimethylpiperidin-4-amine. MS (ESI):mass calcd. for C₂₃H₂₆FN₅O₂S, 455.18; m/z found, 456.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.38 (m, 1H), 8.20 (d, J=1.5, 1H), 8.14-8.10 (m, 1H),7.99-7.94 (m, 1H), 7.76-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.47-7.43 (m,1H), 7.36-7.30 (m, 2H), 3.52-3.45 (m, 2H), 3.26-3.16 (m, 1H), 2.78 (s,6H), 2.55-2.44 (m, 2H), 1.93 (d, J=11.6, 2H), 1.48-1.36 (m, 2H).

Example 74

racemic5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-amine. MS (ESI): masscalcd. for C₂₆H₃₀FN₅O₄S, 427.15; m/z found, 428.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.45 (s, 1H), 8.33 (s, 1H), 8.11-8.07 (m, 1H), 8.03 (m,1H), 7.76-7.70 (m, 1H), 7.67-7.62 (m, 1H), 7.46-7.42 (m, 1H), 7.36-7.29(m, 2H), 3.40-3.41 (m, 1H), 3.13-3.02 (m, 2H), 2.66-2.60 (m, 2H),2.01-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.55-1.42 (m, 2H).

Example 75

N-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand N-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)acetamide. MS (ESI):mass calcd. for C₂₃H₂₄FN₅O₃S, 469.16; m/z found, 470.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.41-8.38 (m, 1H), 8.08 (d, J=1.4, 1H), 8.01-7.97(m, 1H), 7.90 (m, 1H), 7.80 (d, J=7.6, 1H), 7.77-7.72 (m, 1H), 7.68-7.63(m, 1H), 7.46-7.42 (m, 1H), 7.33-7.24 (m, 2H), 3.61-3.50 (m, 1H),3.26-3.18 (m, 2H), 2.59-2.52 (m, 2H), 1.76 (s, 3H), 1.67-1.59 (m, 2H),1.27-1.15 (m, 2H).

Example 76

racemic(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)methanol

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)methanol. MS(ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.33 (d, J=8.7, 2H), 8.10-8.06 (m, 1H), 7.96 (m,1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.36-7.29(m, 2H), 3.43-3.32 (m, 2H), 3.27-3.16 (m, 2H), 2.43-2.34 (m, 1H),2.22-2.14 (m, 1H), 1.68-1.54 (m, 2H), 1.53-1.42 (m, 1H), 1.35-1.21 (m,1H), 1.03-0.91 (m, 1H).

Example 77

racemic tert-Butyl(1-{[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)carbamate

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic tert-butyl(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate. MS (ESI): masscalcd. for C₂₆H₃₀FN₅O₄S, 527.20; m/z found, 528.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.34 (d, J=9.1, 2H), 8.10-8.07 (m, 1H), 8.00 (m, 1H),7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m, 1H), 7.35-7.29 (m,2H), 3.30-3.20 (m, 2H), 3.15-3.06 (m, 1H), 2.51-2.40 (m, 1H), 2.30-2.21(m, 1H), 1.79-1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.39-1.28 (m, 10H),1.26-1.14 (m, 1H).

Example 78

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand2-bromo-N-((1S,2S)-1,3-dihydroxy-1-phenylpropan-2-yl)benzene-sulfonamide.MS (ESI): mass calcd. for C₂₅H₂₃FN₄O₄S, 494.14; m/z found, 495.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=1.4, 1H), 8.10 (s, 1H), 7.87-7.80(m, 2H), 7.55 (t, J=7.5, 1H), 7.43-7.36 (m, 2H), 7.30-7.14 (m, 8H), 4.89(d, J=4.0, 1H), 3.65-3.57 (m, 1H), 3.36 (d, J=1.4, 2H).

Example 79

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (S)-2-bromo-N-(1-hydroxy-4-methylpentan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.29 (d, J=1.4, 1H), 8.16-8.12 (m,1H), 7.98-7.92 (m, 1H), 7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.28(m, 3H), 3.41-3.34 (m, 1H), 3.29-3.22 (m, 2H), 1.59-1.47 (m, 1H),1.35-1.17 (m, 2H), 0.81 (d, J=6.7, 3H), 0.73 (d, J=6.5, 3H).

Example 80

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxypropyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N-(3-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd.for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.37 (d, J=1.2, 1H), 8.30 (s, 1H), 8.08-8.03 (m, 1H), 8.01-7.96(m, 1H), 7.70-7.63 (m, 1H), 7.62-7.56 (m, 1H), 7.42-7.32 (m, 1H),7.36-7.28 (m, 2H), 3.51 (t, J=6.2, 2H), 2.88 (t, J=7.0, 2H), 1.65-1.54(m, 2H).

Example 81

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (S)-2-bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₄H₂₁FN₄O₃S, 464.13; m/z found, 465.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.30 (m, 2H), 8.05-8.01 (m, 1H), 7.85 (t, J=8.2, 1H),7.61-7.56 (m, 1H), 7.50-7.44 (m, 1H), 7.26-7.19 (m, 4H), 7.10-6.97 (m,4H), 4.20 (t, J=6.6, 1H), 3.69-3.58 (m, 2H).

Example 82

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (R)-2-bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₄H₂₁FN₄O₃S, 464.13; m/z found, 465.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.36-8.32 (m, 1H), 8.07-8.01 (m, 2H), 7.75 (t, J=8.2,1H), 7.60-7.54 (m, 1H), 7.49-7.44 (m, 1H), 7.25-7.18 (m, 4H), 7.07-7.00(m, 3H), 6.98-6.92 (m, 1H), 4.19 (t, J=6.6, 1H), 3.69-3.58 (m, 2H).

Example 83

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand2-bromo-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₅H₂₃FN₄O₃S, 478.15; m/z found, 479.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.12-8.05 (m, 2H), 7.89-7.83 (m,1H), 7.67-7.62 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.34 (m, 1H), 7.27-7.12(m, 7H), 4.60 (t, J=4.4, 1H), 3.42-3.34 (m, 1H), 0.91-0.84 (m, 3H).

Example 84

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand2-bromo-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.16-8.13 (m, 1H), 8.06 (d, J=1.4,1H), 7.86 (m, 1H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.28 (m,3H), 3.46-3.35 (m, 2H), 3.13 (q, J=5.4, 1H), 1.60-1.49 (m, 1H),1.48-1.36 (m, 1H), 1.07-0.93 (m, 1H), 0.84-0.74 (m, 6H).

Example 85

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2R)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N-((1R,2R)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.37-8.30 (m, 2H), 8.21-8.16 (m, 1H), 7.97 (m, 1H),7.68-7.62 (m, 1H), 7.60-7.54 (m, 1H), 7.40-7.32 (m, 3H), 3.26-3.18 (m,1H), 2.87-2.79 (m, 1H), 1.94-1.77 (m, 2H), 1.67-1.50 (m, 2H), 1.26-1.09(m, 4H).

Example 86

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (R)-2-bromo-N-(1-hydroxybutan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.32 (m, 2H), 8.16-8.12 (m, 1H), 7.96 (m, 1H),7.68-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.30 (m, 3H), 3.43-3.35 (m,1H), 3.33 (d, J=5.9, 1H), 3.12-3.05 (m, 1H), 1.60-1.48 (m, 1H),1.42-1.28 (m, 1H), 0.79 (t, J=7.4, 3H).

Example 87

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 448 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N-((1R,2S)-2-hydroxycyclohexyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.33 (s, 2H), 8.15-8.11 (m, 1H), 7.98 (m, 1H),7.69-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.42-7.32 (m, 3H), 3.70-3.63 (m,1H), 3.09-3.03 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.44 (m, 3H), 1.42-1.24(m, 3H), 1.22-1.10 (m, 1H).

Example 88

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(40 mg, 0.13 mmol) and 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide (53mg, 0.19 mmol) were added to a 5 mL sealable vial equipped with a stirbar. 1,4-Dioxane (0.7 mL) and Na₂CO₃ (0.3 mL, 2 M) were added. Argon wasbubbled through the solvent while it was rapidly stirred for 10 minbefore adding Pd(dppf)Cl₂.CH₂Cl₂ (5 mg, 0.006 mmol) and heating themixture heated 15 hours at 80° Celsius. The reaction was cooled to rt,diluted with 2 mL of ethylacetate, 2 mL of water and extracted with ofethyl acetate (3×10 mL). The combined organic extracts were then driedwith Na₂SO₄ and concentrated to dryness. The crude product was purifiedby HPLC to give the title compound. MS (ESI): mass calcd. forC₁₈H₁₇FN₄O₃S, 388.10; m/z found, 389.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.43-8.37 (dd, J=2.2, 1.5, 1H), 8.11-8.06 (m, 2H), 7.93-7.86 (m, 1H),7.70-7.64 (m, 1H), 7.62-7.56 (m, 1H), 7.44-7.38 (dd, J=7.6, 1.3, 1H),7.35-7.27 (m, 2H), 3.49-3.44 (t, J=5.9, 2H), 2.90-2.84 (t, J=5.9, 2H).

Example 89

4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-cyclopropylbenzenesulfonamide. MS (ESI): masscalcd. for C₁₉H₁₇FN₄O₂S, 384.11; m/z found, 385.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.39-8.31 (d, J=1.6, 1H), 8.26-8.18 (d, J=1.5, 1H),8.14-8.08 (dd, J=8.0, 1.3, 1H), 7.97-7.89 (m, 1H), 7.73-7.66 (m, 1H),7.65-7.57 (m, 1H), 7.46-7.37 (dd, J=7.6, 1.4, 1H), 7.33-7.23 (m, 3H),2.22-2.13 (m, 1H), 0.50-0.43 (m, 2H), 0.41-0.34 (m, 2H).

Example 90

4′-(5-Aminopyrazin-2-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(cyclopropylmethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.42-8.33 (m, 1H), 8.15-8.10 (dd, J=8.0, 1.3,1H), 8.09-8.06 (d, J=1.5, 1H), 7.91-7.82 (m, 1H), 7.70-7.63 (m, 1H),7.61-7.53 (m, 1H), 7.40-7.35 (dd, J=7.6, 1.4, 1H), 7.25 (s, 1H),7.24-7.21 (m, 1H), 1.21 (m, 3H), 0.50-0.46 (m, 2H), 0.39-0.28 (m, 2H).

Example 91

(R)-(1-((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using(R)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.39-8.34 (m, 1H), 8.24-8.19 (d, J=1.5, 1H), 8.14-8.08(dd, J=8.0, 1.3, 1H), 7.98-7.91 (m, 1H), 7.73-7.66 (m, 1H), 7.65-7.57(m, 1H), 7.46-7.39 (dd, J=7.6, 1.3, 1H), 7.33-7.32 (m, 1H), 7.32-7.27(dd, J=6.0, 1.6, 1H), 3.52-3.45 (m, 1H), 3.41-3.34 (dd, J=11.0, 3.9,1H), 3.24-3.13 (m, 1H), 3.02-2.89 (m, 2H), 1.88-1.73 (m, 3H), 1.71-1.62(dd, J=6.9, 4.6, 1H).

Example 92

(R)-5-(2′-((3-Aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (R)-1-((2-bromophenyl)sulfonyl)pyrrolidin-3-amine,followed by removal of the Boc group with trifluoroacetic acid indichloromethane at rt. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13;m/z found, 414.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.44-8.29 (m, 1H),8.17-8.13 (d, J=1.5, 1H), 8.13-8.09 (dd, J=8.0, 1.3, 1H), 7.99-7.88 (m,1H), 7.79-7.69 (m, 1H), 7.69-7.59 (m, 1H), 7.50-7.42 (dd, J=7.6, 1.4,1H), 7.32 (s, 1H), 7.31-7.29 (dd, J=2.9, 1.5, 1H), 3.77-3.60 (m, 1H),3.29-3.25 (m, 1H), 3.21-3.12 (dd, J=10.9, 6.7, 1H), 3.12-3.01 (dd,J=10.9, 5.0, 1H), 2.98-2.86 (m, 1H), 2.23-2.12 (m, 1H), 1.94-1.78 (m,1H).

Example 93

(S)-5-(2′-((3-Aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (S)-1-((2-bromophenyl)sulfonyl)pyrrolidin-3-amine,followed by removal of the Boc group with trifluoroacetic acid indichloromethane at rt. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13;m/z found, 414.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.43-8.35 (m, 1H),8.16-8.13 (d, J=1.4, 1H), 8.13-8.09 (dd, J=8.0, 1.3, 1H), 7.98-7.90 (m,1H), 7.77-7.71 (m, 1H), 7.68-7.60 (m, 1H), 7.47-7.43 (dd, J=7.5, 1.3,1H), 7.34-7.31 (m, 1H), 7.31-7.29 (q, J=1.5, 1H), 3.73-3.63 (p, J=6.1,1H), 3.29-3.23 (m, 1H), 3.19-3.13 (dd, J=10.8, 6.7, 1H), 3.10-3.03 (dd,J=10.9, 5.0, 1H), 2.98-2.85 (m, 1H), 2.25-2.11 (m, 1H), 1.93-1.80 (m,1H).

Example 94

5-(2′-{[2-(Aminomethyl)pyrrolidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(R)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-2-yl)-methan-amine. MS (ESI):mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.42-8.38 (m, 1H), 8.16-8.13 (dd, J=8.1, 1.3, 1H),8.13-8.12 (d, J=1.5, 1H), 7.94-7.89 (m, 1H), 7.78-7.73 (m, 1H),7.69-7.63 (m, 1H), 7.48-7.45 (dd, J=7.6, 1.3, 1H), 7.36-7.30 (m, 2H),3.71-3.62 (m, 1H), 3.15-3.08 (m, 1H), 3.05-2.98 (m, 1H), 2.86-2.74 (m,2H), 1.92-1.76 (m, 2H), 1.73-1.62 (m, 2H).

Example 95

(S)-(1-((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using(S)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.37-8.34 (m, 1H), 8.24-8.22 (d, J=1.4, 1H), 8.13-8.09(dd, J=8.0, 1.3, 1H), 7.98-7.93 (m, 1H), 7.73-7.67 (m, 1H), 7.63-7.59(m, 1H), 7.44-7.40 (dd, J=7.6, 1.3, 1H), 7.34-7.32 (m, 1H), 7.32-7.30(dd, J=5.9, 1.6, 1H), 3.52-3.45 (dd, J=7.6, 4.0, 1H), 3.40-3.34 (m, 1H),3.22-3.11 (dd, J=10.8, 7.9, 1H), 3.02-2.87 (m, 2H), 1.90-1.72 (m, 3H),1.71-1.62 (dd, J=6.7, 4.5, 1H).

Example 96

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(methylsulfonyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(methylsulfonyl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₇H₁₅FN₄O₄S₂, 422.05; m/z found, 423.0 [M+H]⁺. ¹H NMR(500 MHz, acetone-d₆) δ 8.56 (s, 1H), 8.25-8.18 (dd, J=7.9, 1.4, 1H),8.16 (s, 1H), 7.90-7.84 (m, 1H), 7.64-7.57 (m, 1H), 7.57-7.50 (m, 1H),7.46-7.40 (dd, J=8.2, 1.6, 1H), 7.38-7.31 (d, J=13.3, 1H), 7.31-7.26(dd, J=7.4, 1.4, 1H), 2.96 (s, 3H).

Example 97

(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.37 (s, 1H), 8.27-8.19 (m, 1H), 8.11-8.03 (dd,J=8.0, 1.3, 1H), 7.99-7.91 (m, 1H), 7.72-7.64 (m, 1H), 7.64-7.55 (m,1H), 7.45-7.38 (d, J=7.5, 1H), 7.37-7.27 (m, 2H), 3.74-3.61 (m, 1H),2.80-2.72 (m, 1H), 2.72-2.64 (m, 1H), 1.10-0.99 (d, J=6.2, 3H).

Example 98

(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.41-8.35 (m, 1H), 8.21-8.17 (d, J=1.5, 1H),8.10-8.04 (dd, J=8.0, 1.3, 1H), 7.96-7.91 (m, 1H), 7.71-7.65 (m, 1H),7.62-7.57 (m, 1H), 7.44-7.39 (dd, J=107.5, 1.3, 1H), 7.36-7.29 (m, 2H),3.73-3.60 (m, 1H), 2.77-2.72 (m, 1H), 2.71-2.65 (m, 1H), 1.08-1.03 (d,J=6.3, 3H).

Example 99

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1-hydroxycyclohexyl)methyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1-hydroxycyclohexyl)methyl)-benzene-sulfonamide. MS (ESI):mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) 8.44-8.37 (dd, J=2.2, 1.5, 1H), 8.10-8.04 (m, 2H),7.96-7.87 (m, 1H), 7.71-7.64 (m, 1H), 7.63-7.56 (m, 1H), 7.46-7.39 (dd,J=7.6, 1.4, 1H), 7.37-7.28 (m, 2H), 2.67 (s, 2H), 1.61-1.22 (m, 10H).

Example 100

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.35 (m, 1H), 8.18-8.13 (m, 2H), 7.97-7.90 (m,1H), 7.69-7.63 (m, 1H), 7.60-7.54 (m, 1H), 7.41-7.38 (dd, J=7.7, 1.4,1H), 7.38-7.33 (m, 2H), 3.27 (s, 2H), 1.01 (s, 6H).

Example 101

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2-hydroxy-2-methylpropyl)benzene-sulfonamide. MS (ESI): masscalcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.42-8.38 (dd, J=2.2, 1.4, 1H), 8.10-8.07 (d, J=1.5, 1H),8.07-8.03 (dd, J=7.9, 1.0, 1H), 7.93-7.88 (m, 1H), 7.70-7.64 (m, 1H),7.62-7.57 (m, 1H), 7.44-7.40 (dd, J=7.5, 1.2, 1H), 7.36-7.28 (m, 2H),2.67 (s, 2H), 1.09 (s, 6H).

Example 102

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-1,1-dimethylpropyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(4-hydroxy-2-methylbutan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.40-8.36 (m, 1H), 8.18-8.16 (d, J=1.5, 1H),8.16-8.12 (dd, J=8.0, 1.3, 1H), 7.96-7.89 (m, 1H), 7.68-7.62 (m, 1H),7.60-7.54 (m, 1H), 7.42-7.37 (dd, J=7.6, 1.4, 1H), 7.37-7.35 (m, 1H),7.35-7.32 (dd, J=3.9, 1.6, 1H), 3.61-3.53 (t, J=106.7, 2H), 1.67-1.62(t, J=6.7, 2H), 1.08 (s, 6H).

Example 103

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(3-hydroxy-2,2-dimethylpropyl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.43-8.35 (m, 1H), 8.10-8.06 (d, J=1.5, 1H),8.05-8.02 (dd, J=8.0, 1.3, 1H), 7.95-7.85 (m, 1H), 7.71-7.63 (m, 1H),7.63-7.54 (m, 1H), 7.45-7.39 (dd, J=7.6, 1.3, 1H), 7.38-7.28 (m, 2H),3.19 (s, 2H), 2.62 (s, 2H), 0.77 (s, 6H).

Example 104

(S)-4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide.MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₄S, 418.11; m/z found, 419.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.33 (m, 1H), 8.27-8.23 (d, J=1.4, 1H),8.11-8.05 (dd, J=8.0, 1.3, 1H), 7.99-7.93 (m, 1H), 7.72-7.64 (m, 1H),7.63-7.57 (m, 1H), 7.44-7.39 (dd, J=107.6, 1.4, 1H), 7.38-7.29 (m, 2H),3.62-3.53 (m, 1H), 3.43-3.39 (m, 2H), 2.97-2.90 (dd, J=13.2, 4.8, 1H),2.79-2.71 (dd, J=13.2, 7.0, 1H).

Example 105

(R)-4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide.MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₄S, 418.11; m/z found, 419.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.32 (m, 1H), 8.29-8.22 (d, J=1.4, 1H),8.11-8.05 (dd, J=8.0, 1.3, 1H), 8.00-7.91 (m, 1H), 7.72-7.64 (m, 1H),7.64-7.58 (m, 1H), 7.44-7.40 (dd, J=7.6, 1.3, 1H), 7.37-7.29 (m, 2H),3.61-3.52 (m, 1H), 3.43-3.39 (m, 2H), 2.97-2.90 (dd, J=13.1, 4.8, 1H),2.80-2.72 (dd, J=13.1, 7.0, 1H).

Example 106

(trans)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3,4-diol

The title compound was prepared in a manner similar to that described inExample 88 using(trans)-1-((2-bromophenyl)sulfonyl)pyrrolidine-3,4-diol. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₄S, 430.11; m/z found, 431.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.39-8.34 (m, 1H), 8.24-8.20 (d, J=1.5 Hz, 1H), 8.15-8.08(dd, J=8.0, 1.3 Hz, 1H), 7.97-7.88 (m, 1H), 7.70-7.64 (td, J=7.5, 1.4Hz, 1H), 7.62-7.54 (td, J=7.7, 1.4 Hz, 1H), 7.47-7.38 (dd, J=7.6, 1.3Hz, 1H), 7.34-7.31 (dd, J=8.0, 1.7 Hz, 1H), 7.31-7.27 (dd, J=12.3, 1.7Hz, 1H), 4.00-3.97 (m, 2H), 3.29-3.27 (m, 2H), 3.07-3.03 (m, 2H).

Example 107

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(2-oxopyrrolidin-3-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.38 (dd, J=2.2, 1.4, 1H), 8.26-8.22 (dd,J=8.2, 1.3, 1H), 8.08-8.06 (d, J=1.5, 1H), 7.91-7.84 (m, 1H), 7.70-7.64(m, 1H), 7.61-7.55 (m, 1H), 7.41-7.38 (dd, J=7.6, 1.3, 1H), 7.38-7.32(m, 2H), 3.88-3.81 (dd, J=10.3, 8.3, 1H), 3.28-3.22 (m, 1H), 3.22-3.15(m, 1H), 2.38-2.30 (m, 1H), 1.96-1.86 (m, 1H).

Example 108

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(2-oxopiperidin-3-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 442.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.37 (s, 1H), 8.25-8.15 (m, 2H), 7.97-7.88 (m,1H), 7.71-7.62 (m, 1H), 7.62-7.54 (m, 1H), 7.42-7.30 (m, 3H), 3.67-3.57(dd, J=10.4, 5.8, 1H), 3.22-3.17 (m, 2H), 2.19-2.07 (d, J=10.6, 1H),1.90-1.79 (m, 1H), 1.78-1.64 (m, 2H).

Example 109

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(R)-2-bromo-N-(1-hydroxy-3-methylbutan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.42-8.37 (dd, J=2.2, 1.4, 1H), 8.16-8.11 (dd,J=8.0, 1.3, 1H), 8.10-8.06 (d, J=1.5, 1H), 7.91-7.84 (m, 1H), 7.68-7.61(m, 1H), 7.60-7.53 (m, 1H), 7.39-7.35 (dd, J=7.7, 1.4, 1H), 7.36-7.28(m, 2H), 3.45-3.39 (m, 1H), 3.38-3.33 (m, 1H), 3.10-3.03 (m, 1H),1.89-1.75 (m, 1H), 0.86-0.75 (dd, J=6.9, 4.4, 6H).

Example 110

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 usingtrans-2-bromo-N-(4-hydroxycyclohexyl)benzene-sulfonamide. MS (ESI): masscalcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.40-8.34 (m, 1H), 8.22-8.17 (d, J=1.5, 1H), 8.14-8.08(dd, J=7.9, 1.3, 1H), 7.96-7.90 (m, 1H), 7.69-7.64 (m, 1H), 7.62-7.56(m, 1H), 7.43-7.38 (dd, J=7.7, 1.3, 1H), 7.35-7.28 (m, 2H), 3.43-3.36(m, 1H), 2.89-2.77 (m, 1H), 1.87-1.77 (m, 2H), 1.77-1.68 (dd, J=8.3,4.0, 2H), 1.27-1.05 (m, 4H).

Example 111

(R)-(1-((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-3-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using(R)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-3-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) 8.37 (s, 1H), 8.22-8.19 (d, J=1.5, 1H), 8.14-8.08 (dd,J=8.1, 1.3, 1H), 7.97-7.93 (m, 1H), 7.75-7.66 (m, 1H), 7.65-7.57 (m,1H), 7.45-7.39 (dd, J=7.6, 1.3, 1H), 7.37-7.25 (m, 2H), 3.42-3.36 (m,1H), 3.09-3.03 (dd, J=9.5, 7.5, 1H), 3.03-2.97 (m, 1H), 2.95-2.85 (m,1H), 2.75-2.64 (dd, J=9.6, 7.2, 1H), 2.29-2.17 (m, 1H), 1.86-1.76 (m,1H), 1.54-1.41 (m, 1H).

Example 112

(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using(S)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-3-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.40-8.32 (m, 1H), 8.24-8.17 (d, J=1.5, 1H), 8.12-8.07(dd, J=8.0, 1.3, 1H), 7.99-7.93 (m, 1H), 7.72-7.66 (m, 1H), 7.64-7.58(m, 1H), 7.44-7.40 (dd, J=7.5, 1.3, 1H), 7.35-7.26 (m, 2H), 3.43-3.36(m, 1H), 3.33-3.28 (m, 1H), 3.08-3.03 (dd, J=9.6, 7.6, 1H), 3.03-2.98(m, 1H), 2.94-2.86 (m, 1H), 2.74-2.65 (dd, J=9.6, 7.1, 1H), 2.30-2.13(m, 1H), 1.87-1.74 (m, 1H), 1.56-1.41 (m, 1H).

Example 113

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-bromo-N-(2-oxopiperidin-3-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 442.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.37-8.34 (m, 1H), 8.26-8.19 (m, 2H),7.97-7.91 (m, 1H), 7.69-7.64 (m, 1H), 7.62-7.54 (m, 1H), 7.42-7.34 (m,3H), 3.67-3.58 (dd, J=10.4, 5.9, 1H), 3.22-3.16 (m, 2H), 2.19-2.10 (m,1H), 1.88-1.80 (m, 1H), 1.78-1.64 (m, 2H).

Example 114

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(R)-2-bromo-N-methyl-N-(piperidin-3-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.20-8.16 (dd, J=8.1, 1.3, 1H),8.16-8.14 (d, J=1.5, 1H), 8.00-7.92 (m, 1H), 7.78-7.71 (m, 1H),7.68-7.61 (m, 1H), 7.48-7.43 (dd, J==7.6, 1.3, 1H), 7.37-7.35 (m, 1H),7.35-7.32 (dd, J=7.0, 1.7, 1H), 3.64-3.53 (m, 1H), 3.23-3.17 (d, J=12.8,1H), 3.06-3.00 (t, J=5.9, 1H), 3.00-2.93 (m, 1H), 2.78-2.70 (m, 1H),2.42 (s, 3H), 1.92-1.81 (dd, J=16.5, 3.2, 1H), 1.68-1.57 (m, 1H),1.57-1.44 (m, 1H), 1.44-1.33 (d, J=12.3, 1H).

Example 115

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(S)-2-bromo-N-methyl-N-(piperidin-3-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.43-8.36 (m, 1H), 8.21-8.15 (dd, J=8.1, 1.3, 1H),8.14-8.09 (d, J=101.5, 1H), 7.99-7.90 (m, 1H), 7.78-7.72 (m, 1H),7.67-7.61 (m, 1H), 7.49-7.43 (dd, J=7.6, 1.3, 1H), 7.36-7.35 (m, 1H),7.35-7.32 (dd, J=7.1, 1.7, 1H), 3.64-3.52 (m, 1H), 3.22-3.17 (d, J=13.2,1H), 3.05-3.00 (m, 1H), 3.00-2.93 (m, 1H), 2.79-2.69 (m, 1H), 2.42 (s,3H), 1.93-1.82 (m, 1H), 1.67-1.56 (m, 1H), 1.56-1.45 (m, 1H), 1.43-1.34(m, 1H).

Example 116

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-phenylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(1-hydroxy-3-phenylpropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C₂₅H₂₃FN₄O₃S, 478.15; m/zfound, 479.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.40-8.35 (m, 1H),8.10-8.05 (d, J=1.5, 1H), 7.99-7.95 (dd, J=8.0, 1.3, 1H), 7.86-7.79 (t,J=8.1, 1H), 7.63-7.57 (m, 1H), 7.51-7.45 (m, 1H), 7.31-7.26 (dd, J=7.6,1.3, 1H), 7.19-7.07 (m, 5H), 7.08-7.02 (dd, J=8.0, 1.5, 2H), 3.49-3.41(m, 2H), 3.41-3.34 (m, 1H), 2.92-2.82 (dd, J=13.9, 6.3, 1H), 2.68-2.59(dd, J=13.9, 6.8, 1H).

Example 117

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(R)-2-bromo-N-(2-hydroxy-2-phenylethyl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₄H₂₁FN₄O₃S, 464.13; m/z found, 465.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.33 (m, 1H), 8.11-8.03 (m, 2H), 7.90-7.82 (t,J=8.2, 1H), 7.70-7.63 (m, 1H), 7.61-7.54 (m, 1H), 7.42-7.36 (dd, J=7.6,1.3, 1H), 7.30-7.16 (m, 7H), 4.60-4.53 (dd, J=7.9, 4.8, 1H), 2.98-2.92(m, 1H), 2.92-2.86 (m, 1H).

Example 118

4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylbenzenesulfonamide.MS (ESI): mass calcd. for C₂₆H₂₅FN₄O₃S, 492.16; m/z found, 493.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.35 (m, 1H), 8.16-8.11 (dd, J=8.0, 1.3,1H), 8.10-8.07 (d, J=1.5, 1H), 7.92-7.84 (t, J=8.0, 1H), 7.68-7.61 (m,1H), 7.60-7.54 (m, 1H), 7.40-7.35 (dd, J=7.6, 1.4, 1H), 7.33-7.20 (m,7H), 4.57-4.43 (d, J=8.4, 1H), 3.91-3.79 (m, 1H), 2.49 (s, 3H),0.75-0.62 (d, J=6.8, 3H).

Example 119

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol

The title compound was prepared in a manner similar to that described inExample 88 using 1-((2-bromophenyl)sulfonyl)azetidin-3-ol. MS (ESI):mass calcd. for C₁₉H₁₇FN₄O₃S, 400.10; m/z found, 401.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.40-8.29 (m, 1H), 8.22-8.17 (d, J=1.4, 1H),8.10-8.05 (dd, J=8.0, 1.3, 1H), 7.97-7.91 (m, 1H), 7.75-7.67 (m, 1H),7.64-7.56 (m, 1H), 7.46-7.40 (dd, J=7.5, 1.3, 1H), 7.36-7.27 (m, 2H),4.37-4.25 (m, 1H), 3.70-3.60 (m, 2H), 3.60-3.53 (m, 2H).

Example 120

Racemic-(trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxycyclohexyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 usingracemic-(trans)-2-bromo-N-(2-hydroxycyclohexyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.37 (s, 1H), 8.21-8.16 (m, 2H), 7.95-7.90 (m,1H), 7.68-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.40-7.36 (dd, J=7.6, 1.3,1H), 7.36-7.35 (m, 1H), 7.35-7.32 (dd, J=6.2, 1.6, 1H), 3.25-3.19 (m,1H), 2.86-2.79 (m, 1H), 1.94-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.66-1.58(m, 1H), 1.58-1.51 (m, 1H), 1.26-1.09 (m, 4H).

Example 121

racemic(trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using racemic(trans)-2-bromo-N-(2-(hydroxymethyl)cyclohexyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.40-8.34 (m, 1H), 8.20-8.14 (d, J=1.5, 1H),8.14-8.08 (dd, J=8.1, 1.3, 1H), 7.97-7.88 (m, 1H), 7.70-7.63 (m, 1H),7.63-7.55 (m, 1H), 7.43-7.36 (dd, J=7.7, 1.4, 1H), 7.35-7.25 (m, 2H),3.61-3.52 (dd, J=11.1, 3.7, 1H), 3.43-3.36 (dd, J=11.0, 6.4, 1H),2.92-2.79 (m, 1H), 1.86-1.80 (m, 1H), 1.66-1.53 (m, 3H), 1.34-1.26 (m,1H), 1.18-1.03 (m, 4H).

Example 122

racemic(cis)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using racemiccis-2-bromo-N-(2-(hydroxymethyl)cyclohexyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.37 (m, 1H), 8.16-8.10 (dd, J=8.0, 1.3,1H), 8.09-8.07 (d, J=1.5, 1H), 7.92-7.85 (m, 1H), 7.70-7.63 (m, 1H),7.62-7.55 (m, 1H), 7.43-7.37 (dd, J=7.5, 1.4, 1H), 7.34-7.26 (m, 2H),3.58-3.51 (dd, J=11.1, 7.1, 1H), 3.47-3.39 (m, 1H), 3.38-3.33 (m, 1H),1.69-1.59 (m, 1H), 1.58-1.50 (m, 1H), 1.47-1.16 (m, 7H).

Example 123

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-piperidin-4-ylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(piperidin-4-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.16-8.10 (m, 2H), 7.95-7.89 (m,1H), 7.74-7.66 (m, 1H), 7.64-7.56 (m, 1H), 7.46-7.40 (dd, J=7.7, 1.3,1H), 7.38-7.29 (m, 2H), 3.30-3.22 (m, 2H), 3.21-3.14 (m, 1H), 2.98-2.89(m, 2H), 1.98-1.85 (dd, J=14.6, 3.9, 2H), 1.65-1.48 (m, 2H).

Example 124

5-(2′-{[3-(Aminomethyl)azetidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (1-((2-bromophenyl)sulfonyl)azetidin-3-yl)methanamine.MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.37 (m, 1H), 8.14-8.11 (d, J=1.5, 1H),8.11-8.07 (dd, J=8.0, 1.3, 1H), 7.97-7.90 (m, 1H), 7.76-7.70 (m, 1H),7.65-7.57 (m, 1H), 7.52-7.42 (dd, J=7.7, 1.3, 1H), 7.39-7.25 (m, 2H),3.81-3.67 (t, J=8.1, 2H), 3.42-3.36 (dd, J=8.1, 5.5, 2H), 3.07-3.00 (d,J=7.5, 2H), 2.72-2.59 (m, 1H).

Example 125

4′-(5-Aminopyrazin-2-yl)-N-(azetidin-3-ylmethyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using N-(azetidin-3-ylmethyl)-2-bromobenzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.17-8.12 (d, J=1.5, 1H),8.09-8.05 (dd, J=8.0, 1.3, 1H), 7.97-7.88 (m, 1H), 7.73-7.66 (m, 1H),7.65-7.58 (m, 1H), 7.47-7.41 (dd, J=7.6, 1.4, 1H), 7.36-7.28 (m, 2H),4.02-3.95 (dd, J=11.2, 7.7, 2H), 3.91-3.78 (dd, J=11.3, 6.1, 2H),3.04-2.91 (m, 3H).

Example 126

(R)-5-(3-Fluoro-2′-{[3-(methylamino)pyrrolidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(R)-1-((2-bromophenyl)sulfonyl)-N-methylpyrrolidin-3-amine. MS (ESI):mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.44-8.35 (m, 1H), 8.15-8.08 (m, 2H), 7.98-7.91 (m,1H), 7.78-7.71 (m, 1H), 7.68-7.61 (m, 1H), 7.48-7.43 (dd, J=7.7, 1.3,1H), 7.34-7.27 (m, 2H), 3.69-3.57 (m, 1H), 3.29-3.23 (m, 1H), 3.22-3.16(m, 1H), 3.16-3.11 (m, 1H), 2.99-2.85 (m, 1H), 2.65 (s, 3H), 2.28-2.14(m, 1H), 1.99-1.87 (m, 1H).

Example 127

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(R)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.42-8.38 (dd, J=2.1, 1.5, 1H), 8.13-8.09 (dd, J=8.1,1.3, 1H), 8.09-8.07 (d, J=1.5, 1H), 7.90-7.85 (m, 1H), 7.70-7.64 (m,1H), 7.61-7.55 (m, 1H), 7.41-7.36 (dd, J=7.7, 1.4, 1H), 7.30-7.27 (dd,J=8.0, 1.7, 1H), 7.27-7.22 (dd, J=12.3, 1.7, 1H), 3.91-3.79 (m, 1H),1.24-1.16 (d, J=7.0, 3H).

Example 128

5-[3-Fluoro-2′-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using5-((2-bromophenyl)sulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]-pyridine.MS (ESI): mass calcd. for C₂₂H₁₉FN₆O₂S, 450.13; m/z found, 451.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.40-8.35 (m, 1H), 8.21-8.14 (dd, J=8.1, 1.3,1H), 8.11-8.07 (d, J=1.5, 1H), 7.85-7.79 (m, 1H), 7.76-7.68 (m, 1H),7.65-7.59 (m, 1H), 7.45-7.37 (dd, J=7.5, 1.4, 1H), 7.31-7.14 (m, 3H),4.02-3.88 (m, 2H), 3.28-3.22 (t, J=5.9, 2H), 2.59-2.48 (t, J=5.9, 2H).

Example 129

4-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

The title compound was prepared in a manner similar to that described inExample 88 using4-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)-1H-1,2,4-triazol-5(4H)-one.MS (ESI): mass calcd. for C₂₃H₂₂FN₇O₃S, 495.15; m/z found, 496.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.35 (m, 1H), 8.24-8.22 (d, J=1.5, 1H),8.15-8.11 (dd, J=8.1, 1.3, 1H), 8.01-7.96 (m, 1H), 7.78 (s, 1H),7.76-7.70 (m, 1H), 7.66-7.60 (m, 1H), 7.48-7.43 (dd, J=7.6, 1.3, 1H),7.41-7.33 (m, 2H), 3.88-3.76 (m, 1H), 3.51-3.42 (m, 2H), 2.64-2.53 (m,2H), 1.88-1.79 (d, J=12.3, 2H), 1.68-1.50 (m, 2H).

Example 130

5-(2′-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(1R,4R)-2-((2-bromophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane. MS(ESI): mass calcd. for C₂₁H₂₀FN₅O₂S, 425.13; m/z found, 426.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.42-8.38 (m, 1H), 8.19-8.14 (dd, J=8.1, 1.3,1H), 8.14-8.10 (d, J=1.5, 1H), 7.99-7.91 (m, 1H), 7.79-7.72 (m, 1H),7.68-7.60 (m, 1H), 7.51-7.43 (dd, J=7.6, 1.3, 1H), 7.38-7.35 (m, 1H),7.33 (s, 1H), 4.32 (s, 1H), 4.05 (s, 1H), 3.38-3.33 (m, 1H), 3.30-3.25(m, 1H), 3.21-3.14 (dd, J=11.6, 2.2, 1H), 3.04-2.98 (dd, J=11.0, 2.6,1H), 1.85-1.72 (m, 2H).

Example 131

5-(2′-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(1S,4S)-2-((2-bromophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane. MS(ESI): mass calcd. for C₂₁H₂₀FN₅OO₂S, 425.13; m/z found, 426.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.36 (m, 1H), 8.17-8.14 (m, 2H),8.00-7.92 (m, 1H), 7.79-7.72 (m, 1H), 7.68-7.61 (m, 1H), 7.49-7.45 (dd,J=7.6, 1.3, 1H), 7.39-7.35 (m, 1H), 7.34 (s, 1H), 4.38-4.28 (ml H), 4.05(s, 1H), 3.38-3.32 (dd, J=11.6, 1.7, 1H), 3.30-3.26 (m, 1H), 3.23-3.12(dd, J=11.6, 2.2, 1H), 3.08-2.95 (dd, J=11.0, 2.6, 1H), 1.85-1.74 (m,2H).

Example 132

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-hydroxypentyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(5-hydroxypentyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.44-8.38 (m, 1H), 8.10-8.07 (d, J=1.5, 1H),8.07-8.04 (dd, J=8.0, 1.3, 1H), 7.92-7.87 (m, 1H), 7.68-7.64 (m, 1H),7.62-7.55 (m, 1H), 7.43-7.38 (dd, J=7.6, 1.4, 1H), 7.33-7.27 (m, 2H),3.49-3.45 (t, J=6.6, 2H), 2.78-2.73 (t, J=7.1, 2H), 1.48-1.41 (m, 2H),1.41-1.34 (m, 2H), 1.31-1.21 (m, 2H).

Example 133

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(6-hydroxyhexyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(6-hydroxyhexyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.43-8.38 (m, 1H), 8.09-8.08 (d, J=1.5, 1H),8.08-8.04 (dd, J=7.9, 1.3, 1H), 7.94-7.85 (m, 1H), 7.70-7.63 (m, 1H),7.62-7.56 (m, 1H), 7.43-7.37 (dd, J=7.7, 1.4, 1H), 7.33-7.26 (m, 2H),3.51-3.46 (t, J=6.6, 2H), 2.78-2.72 (t, J=7.1, 2H), 1.51-1.41 (m, 2H),1.42-1.33 (p, J=7.2, 2H), 1.33-1.16 (m, 4H).

Example 134

cis-N-(4-Aminocyclohexyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (cis)-N-(4-aminocyclohexyl)-2-bromobenzenesulfonamide.MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.41-8.36 (m, 1H), 8.19-8.14 (m, 1H),8.13-8.07 (dd, J=8.0, 1.3, 1H), 7.97-7.91 (m, 1H), 7.73-7.67 (m, 1H),7.65-7.58 (m, 1H), 7.46-7.41 (dd, J=7.5, 1.3, 1H), 7.35-7.33 (m, 1H),7.33-7.31 (dd, J=6.2, 1.6, 1H), 3.15-3.00 (m, 2H), 1.80-1.69 (m, 4H),1.68-1.57 (m, 2H), 1.58-1.48 (m, 2H).

Example 135

(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2,3-dihydro-1H-indol-2-yl)-methanol

The title compound was prepared in a manner similar to that described inExample 88 using (S)-(1-((2-bromophenyl)sulfonyl)indolin-2-yl)methanol.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.36-8.33 (m, 1H), 8.22-8.20 (d, J=1.5, 1H),8.19-8.14 (dd, J=8.0, 1.3, 1H), 7.85-7.79 (m, 1H), 7.69-7.63 (m, 1H),7.61-7.56 (m, 1H), 7.32-7.28 (dd, J=7.5, 1.4, 1H), 7.11-7.06 (m, 2H),7.01-6.95 (dd, J=12.2, 1.7, 1H), 6.91-6.80 (m, 3H), 3.85-3.74 (m, 1H),3.67-3.58 (dd, J=10.9, 4.2, 1H), 3.40-3.33 (dd, J=11.0, 7.8, 1H),2.89-2.72 (m, 2H).

Example 136

4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-cyclohexyl-N-(2-hydroxyethyl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₄H₂₇FN₄O₃S, 470.18; m/z found, 471.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.40-8.34 (m, 1H), 8.21-8.18 (d, J=1.5, 1H),8.16-8.12 (dd, J=8.0, 1.4, 1H), 7.99-7.92 (m, 1H), 7.72-7.65 (m, 1H),7.63-7.56 (m, 1H), 7.42-7.38 (dd, J=7.6, 1.4, 1H), 7.35-7.32 (m, 1H),7.32-7.28 (dd, J=5.5, 1.6, 1H), 3.43-3.34 (dd, J=8.0, 6.9, 2H),3.19-3.09 (m, 1H), 2.95-2.87 (dd, J=8.0, 6.9, 2H), 1.73-1.58 (d, J=12.6,2H), 1.58-1.40 (m, 3H), 1.38-1.23 (m, 2H), 1.17-0.93 (m, 3H).

Example 137

(S)-5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (S)-1-((2-bromophenyl)sulfonyl)piperidin-3-amine. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.18-8.14 (d, J=1.5, 1H),8.14-8.08 (dd, J=8.0, 1.3, 1H), 7.97-7.90 (m, 1H), 7.79-7.71 (m, 1H),7.68-7.61 (m, 1H), 7.49-7.42 (dd, J=7.6, 1.4, 1H), 7.33-7.31 (m, 1H),7.31-7.28 (dd, J=5.2, 1.6, 1H), 3.37-3.32 (m, 1H), 3.10-2.98 (m, 2H),2.73-2.62 (m, 1H), 2.62-2.50 (dd, J=12.7, 8.9, 1H), 2.00-1.88 (m, 1H),1.81-1.66 (m, 1H), 1.59-1.33 (m, 2H).

Example 138

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-bis(2-hydroxyethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N,N-bis(2-hydroxyethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₄S, 432.13; m/z found, 433.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.37-8.33 (m, 1H), 8.30-8.25 (d, J=1.4, 1H),8.10-8.05 (dd, J=7.9, 1.3, 1H), 8.01-7.94 (m, 1H), 7.72-7.65 (m, 1H),7.65-7.56 (m, 1H), 7.43-7.38 (dd, J=7.6, 1.4, 1H), 7.34-7.33 (m, 1H),7.32-7.29 (dd, J=5.2, 1.6, 1H), 3.57-3.49 (t, J=106.0, 4H), 3.09-3.01(t, J=6.0, 4H).

Example 139

Racemic1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidine-2-carboxamide

The title compound was prepared in a manner similar to that described inExample 88 using racemic1-((2-bromophenyl)sulfonyl)azetidine-2-carboxamide. MS (ESI): masscalcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.42-8.38 (m, 1H), 8.19-8.13 (m, 1H), 8.09-8.07 (d, J=1.5,1H), 7.93-7.87 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.61 (m, 1H), 7.49-7.43(dd, J=7.6, 1.3, 1H), 7.38-7.31 (m, 2H), 4.57-4.49 (dd, J=9.5, 7.8, 1H),3.80-3.68 (m, 1H), 2.39-2.28 (m, 1H), 2.26-2.15 (m, 1H). (one protonobscured under methanol signal)

Example 140

4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-cyclopropyl-N-(tetrahydro-2H-pyran-4-yl)-benzenesulfonamide.MS (ESI): mass calcd. for C₂₄H₂₅FN₄O₃S, 468.16; m/z found, 469.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.33 (m, 1H), 8.20-8.17 (dd, J=8.0, 1.3,1H), 8.16-8.15 (d, J=1.5, 1H), 7.95-7.90 (m, 1H), 7.74-7.68 (m, 1H),7.66-7.59 (m, 1H), 7.44-7.39 (dd, J=7.6, 1.3, 1H), 7.35-7.27 (m, 2H),3.83-3.75 (dd, J=11.4, 4.3, 2H), 3.52-3.43 (m, 1H), 3.20-3.11 (m, 2H),2.25-2.17 (m, 1H), 1.93-1.81 (m, 2H), 1.26-1.19 (d, J=12.0, 2H),0.54-0.47 (m, 2H), 0.31-0.26 (dd, J=4.0, 2.3, 2H).

Example 141

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2-hydroxyethyl)-N-isopropylbenzene-sulfonamide. MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.40-8.36 (m, 1H), 8.21-8.17 (d, J=1.5, 1H),8.14-8.10 (dd, J=8.0, 1.3, 1H), 8.00-7.91 (m, 1H), 7.72-7.66 (m, 1H),7.63-7.56 (m, 1H), 7.44-7.38 (dd, J=7.5, 1.3, 1H), 7.36-7.27 (m, 2H),3.69-3.55 (m, 1H), 3.43-3.37 (dd, J=7.8, 6.9, 2H), 2.92-2.84 (t, J=7.3,2H), 1.01-0.97 (d, J=6.7, 6H).

Example 142

racemic(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using racemic(4-((2-bromophenyl)sulfonyl)morpholin-2-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₁FN₄O₄S, 444.13; m/z found, 445.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) 8.38-8.34 (m, 1H), 8.24-8.18 (d, J=1.4, 1H), 8.14-8.07 (dd,J=8.0, 1.3, 1H), 7.98-7.92 (m, 1H), 7.76-7.69 (m, 1H), 7.69-7.60 (m,1H), 7.49-7.43 (dd, J==7.6, 1.3, 1H), 7.35 (s, 1H), 7.34-7.31 (dd,J=3.6, 1.5, 1H), 3.78-3.70 (dd, J=11.3, 3.0, 1H), 3.45-3.39 (m, 1H),3.38-3.33 (m, 1H), 3.29-3.25 (m, 1H), 3.22-3.16 (m, 2H), 3.12-3.04 (d,J=12.3, 1H), 2.62-2.49 (m, 1H), 2.45-2.31 (m, 1H).

Example 143

endo-3-((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-amine

The title compound was prepared in a manner similar to that described inExample 88 usingendo-3-((2-bromophenyl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-amine. MS(ESI): mass calcd. for C₂₁H₂₀FN₅O₂S, 425.13; m/z found, 426.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.42-8.38 (m, 1H), 8.16-8.14 (d, J=1.5, 1H),8.11-8.06 (dd, J=8.1, 1.3, 1H), 7.98-7.91 (m, 1H), 7.75-7.69 (m, 1H),7.65-7.59 (m, 1H), 7.46-7.42 (dd, J=7.7, 1.3, 1H), 7.35-7.28 (m, 2H),3.28 (s, 1H), 2.99-2.90 (m, 2H), 2.25-2.16 (t, J=2.3, 1H), 1.90-1.80 (m,2H).

Example 144

(S)-5-(3-Fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (S)-1-((2-bromophenyl)sulfonyl)-2-methylpiperazine. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.37 (m, 1H), 8.23-8.17 (dd, J=8.0, 1.3,1H), 8.15-8.10 (d, J=1.5, 1H), 8.01-7.91 (m, 1H), 7.80-7.73 (m, 1H),7.69-7.60 (m, 1H), 7.53-7.46 (dd, J=7.7, 1.3, 1H), 7.44-7.35 (d, J=9.9,2H), 3.93-3.80 (m 1H), 3.23-3.15 (m, 1H), 3.15-3.03 (m, 3H), 2.79-2.63(m, 2H), 1.21-1.14 (d, J=7.1, 3H).

Example 145

(R)-5-(3-Fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (R)-1-((2-bromophenyl)sulfonyl)-2-methylpiperazine. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.38 (m, 1H), 8.23-8.16 (dd, J=8.1, 1.3,1H), 8.16-8.12 (d, J=1.5, 1H), 8.01-7.95 (m, 1H), 7.80-7.73 (m, 1H),7.68-7.62 (m, 1H), 7.52-7.45 (dd, J=7.6, 1.3, 1H), 7.44-7.36 (m, 2H),3.95-3.79 (dd, J=7.1, 4.4, 1H), 3.23-3.15 (m, 1H), 3.15-3.03 (m, 3H),2.79-2.64 (m, 2H), 1.19-1.15 (d, J=7.1, 3H).

Example 146

(R)-(1-((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperazin-2-yl)methanol

The title compound was prepared in a manner similar to that described inExample 88 using(R)-(1-((2-bromophenyl)sulfonyl)piperazin-2-yl)methanol. MS (ESI): masscalcd. for C₂₁H₂₂FN₅O₃S, 443.14; m/z found, 444.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.43-8.37 (m, 1H), 8.24-8.17 (dd, J=8.0, 1.3, 1H),8.16-8.11 (d, J=1.5, 1H), 8.01-7.94 (m, 1H), 7.82-7.74 (m, 1H),7.69-7.61 (m, 1H), 7.53-7.46 (dd, J=7.7, 1.3, 1H), 7.41 (s, 1H),7.40-7.36 (dd, J=4.3, 1.6, 1H), 3.79-3.64 (m, 3H), 3.49-3.43 (m, 1H),3.43-3.35 (m, 1H), 3.29-3.25 (d, J=3.7, 1H), 3.21-3.11 (m, 1H),2.81-2.70 (m, 1H), 2.70-2.62 (dd, J=13.1, 4.7, 1H).

Example 147

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(1,3-dihydroxy-2-methylpropan-2-yl)-benzene-sulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₄S, 432.13; m/z found, 433.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.37 (dd, J=2.2, 1.5, 1H), 8.20-8.14 (dd,J=8.0, 1.3, 1H), 8.10-8.06 (d, J=1.5, 1H), 7.93-7.84 (m, 1H), 7.69-7.63(m, 1H), 7.60-7.54 (m, 1H), 7.42-7.38 (dd, J=7.5, 1.3, 1H), 7.38-7.32(m, 2H), 3.45-3.39 (m, 2H), 3.39-3.33 (m, 2H), 0.97 (s, 3H).

Example 148

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(S)-2-bromo-N-(1-hydroxy-3-methylbutan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.41-8.38 (d, J=1.7, 1H), 8.15-8.12 (dd, J=8.0,1.3, 1H), 8.09-8.06 (d, J=1.5, 1H), 7.90-7.84 (m, 1H), 7.67-7.61 (m,1H), 7.60-7.54 (m, 1H), 7.39-7.35 (dd, J=7.6, 1.4, 1H), 7.35-7.29 (m,2H), 3.46-3.39 (m, 1H), 3.39-3.33 (m, 1H), 3.09-3.02 (q, J=5.5, 1H),1.90-1.75 (m, 1H), 0.83-0.76 (dd, J=6.9, 4.4, 6H).

Example 149

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(S)-2-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.35 (dd, J=2.2, 1.5, 1H), 8.16-8.11 (dd,J=8.1, 1.3, 1H), 8.10-8.06 (d, J=1.5, 1H), 7.93-7.83 (m, 1H), 7.65-7.59(m, 1H), 7.58-7.52 (m, 1H), 7.37-7.35 (dd, J=3.3, 1.6, 1H), 7.35-7.31(m, 2H), 3.55-3.49 (m, 1H), 3.49-3.43 (m, 1H), 3.11-3.04 (dd, J=5.9,4.2, 1H), 0.82 (s, 9H).

Example 150

(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(R)-2-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.42-8.37 (m, 1H), 8.15-8.11 (dd, J=8.0, 1.3,1H), 8.09-8.05 (d, J=1.5, 1H), 7.92-7.86 (m, 1H), 7.65-7.59 (m, 1H),7.58-7.52 (m, 1H), 7.38-7.35 (dd, J=3.3, 1.5, 1H), 7.35-7.31 (m, 2H),3.55-3.49 (m, 1H), 3.49-3.42 (m, 1H), 3.10-3.04 (dd, J=5.9, 4.2, 1H),0.82 (s, 9H).

Example 151

tert-Butyl[2-({[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]carbamate

The title compound was prepared in a manner similar to that described inExample 88 usingtert-butyl-(2-(2-bromophenylsulfonamido)ethyl)carbamate. MS (ESI): masscalcd. for C₂₃H₂₆FN₅O₄S, 487.17; m/z found, 488.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.57-8.54 (m, 1H), 8.18-8.13 (dd, J=8.0, 1.4, 1H),8.11-8.08 (d, J=1.5, 1H), 8.05-7.98 (m, 1H), 7.65-7.59 (m, 1H),7.58-7.52 (m, 1H), 7.37-7.33 (m, 2H), 7.32-7.29 (dd, J=11.8, 1.7, 1H),4.78 (s, 3H), 4.46 (s, 1H), 3.17-3.04 (d, J=5.9, 2H), 2.97-2.77 (m, 2H),1.38 (s, 9H).

Example 152

N-(2-Aminoethyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using N-(2-aminoethyl)-2-bromobenzenesulfonamide. MS (ESI):mass calcd. for C₁₈H₁₈FN₅O₂S, 387.12; m/z found, 388.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.38 (d, J=1.7, 1H), 8.15-8.11 (d, J=1.5, 1H),8.10-8.06 (dd, J=8.0, 1.3, 1H), 7.98-7.91 (m, 1H), 7.74-7.69 (m, 1H),7.65-7.59 (m, 1H), 7.47-7.43 (dd, J=7.6, 1.3, 1H), 7.33-7.32 (dd, J=4.1,1.8, 1H), 7.31-7.29 (dd, J=8.2, 1.6, 1H), 3.05-2.98 (t, J=5.9, 2H),2.97-2.92 (m, 2H).

Example 153

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxybutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(1-hydroxybutan-2-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.40-8.35 (d, J=1.6, 1H), 8.23-8.17 (d, J=1.5,1H), 8.17-8.10 (dd, J=8.0, 1.3, 1H), 7.97-7.88 (m, 1H), 7.69-7.61 (m,1H), 7.61-7.55 (m, 1H), 7.41-7.36 (dd, J=7.5, 1.4, 1H), 7.36-7.28 (m,2H), 3.43-3.36 (m, 1H), 3.34-3.31 (m, 1H), 3.12-3.05 (m, 1H), 1.60-1.46(m, 1H), 1.42-1.28 (m, 1H), 0.85-0.72 (t, J=7.4, 3H).

Example 154

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(pyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(pyrrolidin-3-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ8.42-8.37 (m, 1H), 8.15-8.10 (m, 2H), 7.96-7.90(m, 1H), 7.75-7.69 (m, 1H), 7.66-7.60 (m, 1H), 7.45 (dd, J=7.6, 1.3 Hz,1H), 7.33 (s, 1H), 7.31 (dd, J=3.7, 1.6 Hz, 1H), 3.74-3.60 (m, 1H),3.33-3.32 (m, 1H), 3.28-3.26 (m, 1H), 3.25-3.18 (m, 1H), 3.11 (dd,J=12.3, 5.4 Hz, 1H), 2.17-2.04 (m, 1H), 1.85-1.73 (m, 1H).

Example 155

N-[2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]acetamide

The title compound was prepared in a manner similar to that described inExample 88 using N-(2-(2-bromophenylsulfonamido)ethyl)acetamide. MS(ESI): mass calcd. for C₂₀H₂₀FN₅O₃S, 429.13; m/z found, 430.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.39-8.33 (m, 1H), 8.28-8.25 (d, J=1.4, 1H),8.09-8.03 (dd, J=8.0, 1.3, 1H), 8.00-7.93 (m, 1H), 7.70-7.65 (dd, J=7.5,1.4, 1H), 7.63-7.56 (m, 1H), 7.43-7.39 (dd, J=157.5, 1.4, 1H), 7.36-7.28(m, 2H), 3.19-3.12 (t, J=6.3, 2H), 2.89-2.83 (t, J=6.3, 2H), 1.86 (s,3H).

Example 156

(S)-2-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)propanoicacid

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-(2-bromophenylsulfonamido)propanoic acid. MS(ESI): mass calcd. for C₁₉H₁₇FN₄O₄S, 416.10; m/z found, 417.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.39-8.34 (m, 1H), 8.23-8.20 (d, J=1.4, 1H),8.13-8.08 (dd, J=8.0, 1.3, 1H), 7.96-7.89 (m, 1H), 7.69-7.62 (m, 1H),7.60-7.54 (m, 1H), 7.39-7.36 (dd, J=7.6, 1.3, 1H), 7.36-7.34 (dd, J=8.0,1.7, 1H), 7.34-7.30 (dd, J=12.3, 1.7, 1H), 3.77-3.66 (q, J=7.2, 1H),1.33-1.25 (d, J=7.2, 3H).

Example 157

4′-(5-Aminopyrazin-2-yl)N—N-[2-(carbamoylamino)ethyl]-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(2-ureidoethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₉FN₆O₃S, 430.12; m/z found, 431.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.38-8.32 (m, 1H), 8.29 (s, 1H), 8.09-8.03 (dd,J=8.0, 1.3, 1H), 8.01-7.93 (m, 1H), 7.73-7.64 (m, 1H), 7.64-7.55 (m,1H), 7.45-7.38 (dd, J=7.6, 1.4, 1H), 7.37-7.28 (m, 2H), 3.15-3.04 (t,J=6.2, 2H), 2.87-2.78 (t, J=6.2, 2H).

Example 158

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.34 (m, 1H), 8.29-8.24 (dd, J=8.0, 1.3,1H), 8.07-8.05 (d, J=1.5, 1H), 7.84-7.79 (m, 1H), 7.71-7.66 (m, 1H),7.63-7.58 (m, 1H), 7.42-7.37 (dd, J=7.6, 1.3, 1H), 7.31-7.23 (m, 2H),7.21-7.13 (m, 2H), 7.12-7.07 (m, 1H), 7.03-6.97 (m, 1H), 4.49-4.45 (d,J=5.3, 1H), 4.28-4.22 (m, 1H), 3.19-3.11 (dd, J=15.8, 6.7, 1H),2.70-2.64 (dd, J=15.8, 5.9, 1H).

Example 159

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1′,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.34 (m, 1H), 8.29-8.25 (dd, J=8.1, 1.3,1H), 8.07-8.04 (d, J=1.5, 1H), 7.86-7.78 (m, 1H), 7.73-7.65 (m, 1H),7.65-7.57 (m, 1H), 7.44-7.36 (dd, J=7.6, 1.3, 1H), 7.32-7.23 (m, 2H),7.22-7.12 (m, 2H), 7.12-7.06 (m, 1H), 7.02-6.95 (d, J=7.6, 1H),4.51-4.43 (d, J=5.4, 1H), 4.30-4.21 (m, 1H), 3.20-3.10 (dd, J=15.9, 6.7,1H), 2.72-2.58 (dd, J=15.8, 6.0, 1H).

Example 160

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.39-8.33 (m, 1H), 8.27-8.22 (dd, J=8.0, 1.3,1H), 8.08-8.04 (d, J=1.5, 1H), 7.88-7.80 (m, 1H), 7.72-7.67 (m, 1H),7.65-7.58 (m, 1H), 7.42-7.37 (dd, J=7.7, 1.4, 1H), 7.31-7.26 (dd, J=8.0,1.7, 1H), 7.26-7.21 (dd, J=12.2, 1.7, 1H), 7.20-7.16 (dd, J=4.7, 1.2,2H), 7.12-7.05 (m, 1H), 7.06-7.01 (m, 1H), 4.64-4.56 (dd, J=5.1, 1.0,1H), 4.30-4.24 (m, 1H), 3.01-2.93 (dd, J=16.2, 5.2, 1H), 2.80-2.72 (dd,J=16.2, 2.6, 1H).

Example 161

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.32 (m, 1H), 8.28-8.21 (dd, J=8.0, 1.3,1H), 8.09-8.02 (d, J=1.5, 1H), 7.88-7.79 (m, 1H), 7.73-7.66 (m, 1H),7.65-7.57 (m, 1H), 7.42-7.38 (dd, J=7.6, 1.4, 1H), 7.30-7.26 (dd, J=8.0,1.7, 1H), 7.26-7.21 (dd, J=12.2, 1.7, 1H), 7.20-7.16 (dd, J=4.7, 1.2,2H), 7.11-7.05 (m, 1H), 7.06-7.01 (m, 1H), 4.62-4.55 (d, J=5.3, 1H),4.30-4.21 (m, 1H), 3.04-2.92 (dd, J=16.2, 5.2, 1H), 2.81-2.72 (dd,J=16.1, 2.6, 1H).

Example 162

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-((1S,2S)-2-hydroxycyclohexyl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.36 (s, 1H), 8.26-8.22 (d, J=1.5, 2H), 8.22-8.15(dd, J=8.0, 1.3, 2H), 7.97-7.90 (m, 2H), 7.69-7.62 (m, 2H), 7.61-7.54(m, 2H), 7.41-7.32 (m, 5H), 3.25-3.18 (m, 1H), 2.88-2.77 (m, 2H),1.96-1.84 (m, 2H), 1.85-1.77 (m, 2H), 1.68-1.59 (m, 2H), 1.59-1.49 (m,2H), 1.25-1.18 (m, 4H), 1.18-1.11 (m, 3H).

Example 163

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[6-(trifluoromethyl)pyridin-3-yl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(6-(trifluoromethyl)pyridin-3-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₁₅F₄N₅O₂S, 489.09; m/z found, 490.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.43-8.38 (m, 1H), 8.29-8.24 (dd, J=8.0, 1.4,1H), 8.11-8.08 (d, J=1.5, 1H), 8.08-8.06 (d, J=2.6, 1H), 7.87-7.80 (m,1H), 7.72-7.67 (m, 1H), 7.67-7.61 (m, 1H), 7.58-7.52 (d, J=8.7, 1H),7.46-7.42 (dd, J=8.7, 2.5, 1H), 7.38-7.33 (dd, J=7.5, 1.4, 1H),7.16-7.10 (dd, J=12.1, 1.7, 1H), 7.10-7.05 (dd, J=8.0, 1.7, 1H).

Example 164

5-(3-Fluoro-2′-{[4-(1H-imidazol-4-yl)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using1-((2-bromophenyl)sulfonyl)-4-(1H-imidazol-4-yl)piperidine. MS (ESI):mass calcd. for C₂₄H₂₃FN₆O₂S, 478.16; m/z found, 479.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.83-8.76 (d, J=1.4, 1H), 8.39-8.33 (m, 1H),8.16-8.08 (m, 2H), 7.98-7.85 (m, 1H), 7.75-7.68 (m, 1H), 7.65-7.60 (m,1H), 7.48-7.41 (dd, J=7.5, 1.3, 1H), 7.34 (s, 1H), 7.32-7.31 (m, 1H),7.30-7.26 (d, J=1.2, 1H), 3.48-3.39 (d, J=13.3, 2H), 2.84-2.69 (m, 1H),2.64-2.48 (m, 2H), 1.93-1.80 (d, J=12.9, 2H), 1.52-1.33 (m, 2H).

Example 165

N-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 usingN-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-bromobenzenesulfonamide. MS(ESI): mass calcd. for C₂₂H₂₀FN₇O₂S, 465.14; m/z found, 466.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.36 (s, 1H), 8.26-8.18 (d, J=1.4, 1H), 8.12-8.06(d, J=7.9, 1H), 7.98-7.92 (m, 1H), 7.90 (s, 1H), 7.76-7.69 (m, 1H),7.68-7.59 (m, 1H), 7.48-7.41 (dd, J=7.6, 1.4, 1H), 7.39-7.29 (m, 2H),3.88 (s, 2H), 2.50 (s, 3H).

Example 166

4′-(5-Aminopyrazin-2-yl)-N-(2,6-dimethoxypyrimidin-4-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2,6-dimethoxypyrimidin-4-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₁₉FN₆O₄S, 482.12; m/z found, 483.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.36 (m, 1H), 8.28-8.20 (d, J=8.0, 1H),8.10-8.06 (d, J=1.5, 1H), 7.84-7.77 (m, 1H), 7.66-7.52 (m, 3H),7.34-7.29 (d, J=7.3, 1H), 7.14-7.05 (m, 2H), 3.75 (s, 3H), 3.60 (s, 3H).

Example 167

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-methylpyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(5-methylpyrazin-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₁H₁₇FN₆O₂S, 436.11; m/z found, 437.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.25-8.21 (dd, J=8.1, 1.0,1H), 8.10-8.07 (d, J=1.5, 1H), 7.94-7.85 (m, 2H), 7.82-7.76 (m, 1H),7.67-7.60 (m, 1H), 7.61-7.54 (m, 1H), 7.34-7.27 (m, 1H), 7.15-7.05 (m,2H), 2.23 (s, 3H).

Example 168

(S)-2-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)-4-methylpentanamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-(2-bromophenylsulfonamido)-4-methylpentanamide.MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₃S, 457.16; m/z found, 458.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.37 (m, 1H), 8.13-8.09 (dd, J=8.0, 1.3,1H), 8.09-8.06 (d, J=1.5, 1H), 7.90-7.85 (m, 1H), 7.69-7.62 (m, 1H),7.59-7.53 (m, 1H), 7.40-7.36 (dd, J=7.6, 1.3, 1H), 7.36-7.29 (m, 2H),3.79-3.73 (dd, J=9.1, 5.7, 1H), 1.72-1.54 (m, 1H), 1.51-1.34 (m, 2H),0.88-0.84 (d, J=6.6, 3H), 0.81-0.78 (d, J=6.6, 3H).

Example 169

4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(2-cyanoethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₆FN₅O₂S, 397.10; m/z found, 398.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.39-8.34 (m, 1H), 8.21-8.17 (d, J=1.5, 1H),8.09-8.06 (dd, J=8.0, 1.3, 1H), 7.96-7.90 (m, 1H), 7.72-7.66 (m, 1H),7.64-7.57 (m, 1H), 7.43-7.39 (dd, J=7.7, 1.4, 1H), 7.37-7.27 (m, 2H),3.09-3.02 (t, J=6.6, 2H), 2.56-2.50 (t, J=6.6, 2H).

Example 170

(R)-4′-(5-Aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-bromo-N-(1-cyanopropan-2-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₂S, 411.12; m/z found, 412.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.36 (m, 1H), 8.17-8.14 (d, J=1.4, 1H),8.14-8.10 (dd, J=8.0, 1.3, 1H), 7.96-7.87 (m, 1H), 7.72-7.65 (m, 1H),7.63-7.56 (m, 1H), 7.44-7.38 (dd, J=7.7, 1.4, 1H), 7.37-7.29 (m, 2H),3.47-3.39 (dd, J=12.3, 6.1, 1H), 2.61-2.46 (m, 2H), 1.18-1.11 (d, J=6.7,3H).

Example 171

(S)-4′-(5-Aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-bromo-N-(1-cyanopropan-2-yl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₂S, 411.12; m/z found, 412.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.42-8.38 (dd, J=2.2, 1.5, 1H), 8.16-8.09 (dd,J=8.0, 1.3, 1H), 8.09-8.07 (d, J=1.5, 1H), 7.93-7.86 (m, 1H), 7.71-7.65(m, 1H), 7.64-7.56 (m, 1H), 7.45-7.38 (dd, J=7.5, 1.3, 1H), 7.37-7.28(m, 2H), 3.51-3.37 (m, 1H), 2.64-2.45 (m, 2H), 1.18-1.11 (d, J=6.7, 3H).

Example 172

4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2-cyanoethyl)-N-cyclopropylbenzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₀FN₅O₂S, 437.13; m/z found, 438.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.34 (d, J=1.6, 1H), 8.23-8.18 (d, J=1.4, 1H),8.18-8.13 (dd, J=8.0, 1.3, 1H), 8.00-7.92 (m, 1H), 7.76-7.71 (m, 1H),7.68-7.60 (m, 1H), 7.43-7.38 (dd, J=7.6, 1.3, 1H), 7.22 (s, 1H),7.21-7.19 (dd, J=4.4, 1.5, 1H), 3.02-2.95 (t, J=6.7, 2H), 2.62-2.55 (t,J=6.7, 2H), 2.52-2.35 (m, 1H), 0.63-0.52 (m, 2H), 0.42-0.34 (m, 2H).

Example 173

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-methyloxetan-3-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-(3-methyloxetan-3-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.38 (s, 1H), 8.17 (s, 1H), 8.14-8.08 (d, J=8.0,1H), 7.97-7.88 (m, 1H), 7.73-7.65 (m, 1H), 7.65-7.55 (m, 1H), 7.47-7.38(d, J=7.6, 1H), 7.37-7.25 (m, 2H), 4.57-4.49 (d, J=6.3, 2H), 4.20-4.13(d, J=6.2, 2H), 1.46 (s, 3H).

Example 174

3-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)propanenitrile

The title compound was prepared in a manner similar to that described inExample 88 using3-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)propanenitrile. MS (ESI):mass calcd. for C₂₃H₂₃FN₆O₂S, 466.16; m/z found, 467.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.40-8.38 (m, 1H), 8.15-8.11 (m, 2H), 8.00-7.92 (m,1H), 7.78-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.49-7.43 (dd, J=7.6, 1.3,1H), 7.34-7.32 (d, J=0.9, 1H), 7.32-7.30 (dd, J=3.7, 1.6, 1H), 3.13-3.07(t, J=7.1, 2H), 3.07-3.02 (t, J=4.7, 4H), 2.87-2.81 (d, J=4.8, 4H),2.81-2.76 (t, J=7.0, 2H).

Example 175

(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methoxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using(S)-2-bromo-N-(1-methoxypropan-2-yl)benzene-sulfonamide. MS (ESI): masscalcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.42-8.37 (m, 1H), 8.16-8.11 (dd, J=8.0, 1.3, 1H),8.10-8.06 (d, J=1.5, 1H), 7.91-7.86 (m, 1H), 7.70-7.62 (m, 1H),7.61-7.53 (m, 1H), 7.42-7.36 (dd, J=7.5, 1.4, 1H), 7.35-7.26 (m, 2H),3.37-3.31 (m, 1H), 3.22-3.18 (m, 1H), 3.17 (s, 3H), 3.15-3.10 (m, 1H),1.06-1.00 (d, J=6.7, 3H).

Example 176

5-{3-Fluoro-2′-[(4-pyrazin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)pyrazine.MS (ESI): mass calcd. for C₂₄H₂₂FN₇O₂S, 491.15; m/z found, 492.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.38-8.32 (m, 1H), 8.23-8.17 (d, J=1.4, 1H),8.16-8.10 (m, 2H), 8.09-8.05 (m, 1H), 7.97-7.90 (m, 1H), 7.80-7.76 (d,J=2.7, 1H), 7.75-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.47-7.42 (dd, J=7.6,1.3, 1H), 7.36-7.33 (dd, J=5.1, 1.6, 1H), 7.33 (s, 1H), 3.53-3.39 (t,J=5.1, 4H), 3.02-2.95 (t, J=5.1, 4H).

Example 177

5-{3-Fluoro-2′-[(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)pyrimidine. MS (ESI): masscalcd. for C₂₄H₂₂FN₇O₂S, 491.15; m/z found, 492.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.39 (s, 1H), 8.29-8.23 (d, J=4.7, 2H), 8.16-8.10 (d,J=8.0, 1H), 8.08 (s, 1H), 7.95-7.87 (m, 1H), 7.76-7.68 (m, 1H),7.66-7.57 (m, 1H), 7.50-7.42 (d, J=7.5, 1H), 7.34-7.32 (d, J=3.6, 1H),7.31 (s, 1H), 6.68-6.51 (t, J=4.8, 1H), 3.73-3.56 (t, J=5.0, 4H),2.97-2.85 (t, J=4.9, 4H).

Example 178

5-(2′-Amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromoaniline. MS (ESI): mass calcd. for C₁₆H₁₃FN₄, 280.11; m/zfound, 281.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.02 (s,1H), 7.91 (m, 1H), 7.31 (d, J=12.7, 2H), 7.04 (d, J=7.3, 2H), 6.82-6.58(m, 4H), 4.94 (s, 2H).

Example 179

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 584 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in StepB. MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.42 (s, 1H), 8.39 (s, 1H), 8.18 (d,J=7.3, 1H), 8.08 (m, 1H), 7.66-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.43(dd, J=8.1, 1.8, 1H), 7.38-7.32 (m, 2H), 4.12 (s, 1H), 3.49 (s, 2H),1.64-1.39 (m, 8H).

Example 180

racemic1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3-phenylpyrrolidin-3-ol

The title compound was prepared in a manner similar to that described inExample 584 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand racemic 1-((2-bromophenyl)sulfonyl)-3-phenylpyrrolidin-3-ol in StepB. MS (ESI): mass calcd. for C₂₆H₂₃FN₄O₃S, 490.15; m/z found, 491.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (s, 1H), 8.20 (d, J=9.2, 1H),8.11 (d, J=1.5, 1H), 8.00 (t, J=8.1, 1H), 7.61 (dd, J=7.5, 6.2, 1H),7.53 (m, 1H), 7.40-7.34 (m, 3H), 7.34-7.28 (m, 5H), 4.68 (s, 2H),3.41-3.23 (m, 4H), 3.18 (d, J=10.8, 1H), 2.21-2.11 (m, 1H), 2.10-2.01(m, 1H).

Example 181

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand N-(2-bromophenyl)pyrrolidine-1-sulfonamide in Step B. MS (ESI): masscalcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.40 (dd, J=5.4, 1.4, 2H), 8.14 (m, 1H), 7.61 (dd, J=8.3,1.1, 1H), 7.42-7.35 (m, 1H), 7.32 (dd, J=8.0, 1.7, 1H), 7.23 (dd, J=3.6,1.6, 1H), 7.22-7.15 (m, 1H), 6.44 (s, 1H), 3.33-3.25 (m, 4H), 1.87 (dd,J=7.0, 0.9, 4H).

Example 182

N′-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand N-(2-bromophenyl)-N,N-dimethylsulfonamide in Step B. MS (ESI): masscalcd. for C₁₈H₁₈FN₅O₂S, 387.12; m/z found, 388.3 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.60 (dd, J=2.3, 1.4, 1H), 8.12 (d, J=1.5, 1H), 8.07 (m,1H), 7.61 (dd, J=8.3, 1.1, 1H), 7.40-7.34 (m, 1H), 7.29-7.26 (m, 1H),7.25-7.24 (m, 1H), 7.21-7.16 (m, 2H), 6.42 (s, 1H), 4.72 (s, 2H), 2.79(s, 6H).

Example 183

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O₃S, 429.13; m/z found, 430.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.45 (s, 1H), 8.34 (d, J=1.4, 1H), 8.14 (m, 1H), 7.63 (d, J=8.0, 1H),7.43-7.35 (m, 1H), 7.31 (dd, J=8.0, 1.7, 1H), 7.24-7.19 (m, 2H), 6.39(s, 1H), 3.67 (dd, J=5.8, 3.7, 4H), 3.23-3.14 (m, 4H).

Example 184

(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-oltrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand (S)-1-((2-bromophenyl)sulfonyl)pyrrolidin-3-ol in Step B. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.44 (d, J=1.3, 1H), 8.33 (d, J=1.5, 1H), 8.13 (dd,J=7.9, 1.3, 1H), 8.07 (m, 1H), 7.62 (m, 1H), 7.58-7.52 (m, 1H),7.41-7.29 (m, 3H), 4.44-4.36 (m, 1H), 3.23-3.15 (m, 3H), 3.07-2.99 (m,1H), 1.98-1.88 (m, 1H), 1.88-1.78 (m, 1H).

Example 185

(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-oltrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand (R)-1-((2-bromophenyl)sulfonyl)pyrrolidin-3-ol in Step B. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.43 (d, J=1.4, 1H), 8.33 (d, J=1.5, 1H), 8.13 (dd,J=7.7, 1.3, 1H), 8.07 (m, 1H), 7.62 (m, 1H), 7.55 (m, 1H), 1.98-1.88 (m,1H), 7.42-7.29 (m, 3H), 3.24-3.15 (m, 3H), 3.04 (t, J=1.5, 1H), 1.86 (s,1H), 4.44-4.35 (m, 1H).

Example 186

Racemic-1′-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-1,3′-bipyrrolidin-4′-ol

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand Racemic-1′-((2-bromophenyl)sulfonyl)-[1,3′-bipyrrolidin]-4′-ol inStep B. MS (ESI): mass calcd. for C₂₄H₂₆FN₅O₃S, 483.17; m/z found, 484.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.60-8.57 (m, 1H), 8.15 (d, J=6.8,1H), 8.11 (d, J=1.5, 1H), 7.97 (m, 1H), 7.61 (dd, J=7.5, 6.1, 1H),7.55-7.49 (m, 1H), 7.38-7.28 (m, 3H), 4.68 (s, 2H), 4.18-4.12 (m, 1H),3.30 (dd, J=10.5, 6.2, 1H), 3.23 (dd, J=10.1, 6.8, 1H), 2.95 (dd,J=10.0, 6.4, 1H), 2.88 (dd, J=10.4, 4.4, 1H), 2.63-2.57 (m, 1H),2.52-2.38 (m, 5H), 1.74-1.67 (m, 4H).

Example 187

Racemic-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-morpholin-4-ylpyrrolidin-3-oltrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand Racemic-1-((2-bromophenyl)sulfonyl)-4-morpholinopyrrolidin-3-ol inStep B. MS (ESI): mass calcd. for C₂₄H₂₆FN₅O₄S, 499.17; m/z found, 500.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.41 (s, 1H), 8.32 (s, 1H), 8.13-8.09(m, 1H), 7.99 (m, 1H), 7.70-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.38 (dd,J=7.5, 1.3, 1H), 7.35-7.30 (m, 2H), 4.72-4.63 (m, 2H), 3.94-3.85 (m,3H), 3.40-3.25 (m, 3H), 3.22-3.10 (m, 3H), 3.05-2.94 (m, 2H), 2.92-2.84(m, 2H), 2.08-2.02 (m, 2H).

Example 188

Racemic-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(4-methylpiperazin-1-yl)-pyrrolidin-3-oltrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineandRacemic-1-((2-bromophenyl)sulfonyl)-4-(4-methylpiperazin-1-yl)pyrrolidin-3-olin Step B. MS (ESI): mass calcd. for C₂₅H₂₉FN₆O₃S, 512.20; m/z found,513.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 6.90-6.87 (m, 1H), 6.63-6.57 (m,2H), 6.45-6.40 (m, 1H), 6.23-6.17 (m, 1H), 6.12-6.07 (m, 1H), 5.95-5.89(m, 1H), 5.83-5.76 (m, 2H), 2.58-2.50 (m, 1H), 2.46 (s, 2H), 1.84-1.81(m, 2H), 1.77-1.72 (m, 2H), 1.63-1.58 (m, 1H), 1.32 (s, 3H), 1.31-1.26(m, 1H), 1.23-1.13 (m, 3H),

Example 189

5-{3-Fluoro-2′-[(trifluoromethyl)sulfanyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-trifluorothiomethylbromobenzene. MS (ESI): mass calcd. forC₁₇H₁₁F₄N₃S, 365.06; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.46-8.37 (m, 1H), 8.09 (d, J=1.3, 1H), 7.93 (m, 1H), 7.87 (d, J=7.7,1H), 7.69-7.60 (m, 1H), 7.55-7.50 (m, 2H), 7.28-7.17 (m, 2H).

Example 190

5-[2′-(tert-Butylsulfanyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in The title compound was prepared using analogous conditionsto those described in Example 6 utilizing(2-bromophenyl)(tert-butyl)sulfane. MS (ESI): mass calcd. forC₂₀H₂₀FN₃S, 353.14; m/z found, 354.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ8.44-8.36 (m, 1H), 8.10-8.03 (d, J=1.5, 1H), 7.93-7.86 (m, 1H),7.73-7.65 (dd, J=7.8, 1.4, 1H), 7.56-7.49 (m, 1H), 7.49-7.41 (m, 2H),7.34-7.25 (m, 2H), 1.99 (s, 1H), 1.02 (s, 9H).

Example 191

5-[2′-(Ethylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand N-(2-bromophenyl)ethane-1-sulfonamide. MS (ESI): mass calcd. forC₁₈H₁₆FN₃O₂S, 357.09; m/z found, 358.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.48-8.36 (m, 1H), 8.16 (dd, J=7.9, 1.3, 1H), 8.09 (d, J=1.4, 1H), 7.94(m, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.48 (dd, J=7.5, 1.3, 1H), 7.34 (s,1H), 7.31 (d, J=2.4, 1H), 2.84 (q, J=7.4, 2H), 1.06 (t, J=7.4, 3H).

Example 192

5-[3-Fluoro-2′-(propylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(propylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₉H₁₈FN₃O₂S, 371.11; m/z found, 372.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.40 (s, 1H), 8.14 (d, J=1.2, 1H), 8.08 (dd, J=7.8, 1.1, 1H), 7.95 (m,1H), 7.81 (m, 1H), 7.72 (m, 1H), 7.48 (dd, J=7.4, 1.1, 1H), 7.38 (dd,J=12.4, 1.4, 1H), 7.32 (dd, J=8.0, 1.6, 1H), 2.94-2.81 (m, 2H),1.49-1.32 (m, 2H), 0.79 (t, J=7.4, 3H).

Example 193

5-{3-Fluoro-2′-[(2-methylpropyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(isobutylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₀H₂₀FN₃O₂S, 385.13; m/z found, 386.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.42 (s, 1H), 8.12 (dd, J=7.9, 1.1, 1H), 8.05 (d, J=1.4, 1H), 7.96 (m,1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.49 (dd, J=7.5, 1.0, 1H), 7.37 (dd,J=12.4, 1.5, 1H), 7.32 (dd, J=8.0, 1.6, 1H), 6.76 (s, 2H), 2.81 (d,J=6.4, 2H), 1.85-1.75 (m, 1H), 0.82 (d, J=6.7, 6H).

Example 194

5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing 1-bromo-2-(tert-butylsulfonyl)benzene.MS (ESI): mass calcd. for C₂₀H₂₀FN₃O₂S, 385.13; m/z found, 386.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.51-8.44 (d, J=1.4, 1H), 8.27-8.20 (d, J=1.4,1H), 8.10-8.04 (dd, J=8.0, 1.4, 1H), 8.04-7.98 (m, 1H), 7.70-7.63 (m,1H), 7.62-7.55 (m, 1H), 7.36-7.30 (dd, J=7.6, 1.4, 1H), 7.29-7.25 (dd,J=8.1, 1.7, 1H), 7.22-7.17 (dd, J=12.3, 1.7, 1H), 1.23-1.11 (s, 9H).

Example 195

5-[2′-(Cyclopentylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(cyclopentylsulfonyl)benzene MS (ESI): mass calcd. forC₂₁H₂₀FN₃O₂S, 397.13; m/z found, 398.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.65 (d, J=1.3, 1H), 8.30 (d, J=1.3, 1H), 8.19 (dd, J=7.9, 1.2, 1H),8.14 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.48 (dd, J=7.5, 1.2, 1H),7.42 (s, 1H), 7.41-7.38 (m, 1H), 3.23-3.15 (m, 1H), 1.92-1.81 (m, 2H),1.77-1.63 (m, 4H), 1.60-1.51 (m, 2H).

Example 196

5-[2′-(Cyclobutylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(cyclobutylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₀H₁₈FN₃O₂S, 383.11; m/z found, 384.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.44 (s, 1H), 8.17 (dd, J=7.9, 1.1, 1H), 8.13 (d, J=1.4, 1H), 7.96 (m,1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.34 (s,1H), 7.31 (dd, J=6.4, 1.5, 1H), 3.65-3.53 (m, 1H), 2.39-2.26 (m, 2H),2.08-1.98 (m, 2H), 1.98-1.87 (m, 2H).

Example 197

5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₉H₁₆FN₃O₂S, 369.09; m/z found, 370.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.55-8.49 (m, 1H), 8.33 (s, 1H), 8.13 (dd, J=8.0, 1.2, 1H), 8.11-8.05(m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.48 (dd, J=7.6, 1.1, 1H),7.43-7.36 (m, 2H), 2.35-2.26 (m, 1H), 1.04-0.91 (m, 4H).

Example 198

5-[3-Fluoro-2′-(hexylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(hexylsulfonyl)benzene MS (ESI): mass calcd. forC₂₂H₂₄FN₃O₂S, 413.16; m/z found, 414.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.66 (s, 1H), 8.31 (s, 1H), 8.21-8.13 (m, 2H), 7.81 (m, 1H), 7.72 (m,1H), 7.49 (dd, J=7.6, 1.2, 1H), 7.43 (dd, J=3.6, 1.4, 1H), 7.40 (s, 1H),2.89-2.80 (m, 2H), 1.50 (m, 2H), 1.31-1.11 (m, 6H), 0.85 (t, J=7.1, 3H).

Example 199

5-{3-Fluoro-2′-[(1-methylethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(isopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₉H₁₈FN₃O₂S, 371.11; m/z found, 372.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.42 (s, 1H), 8.15 (dd, J=8.0, 1.1, 1H), 8.09 (d, J=1.4, 1H), 7.93 (m,1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.51-7.44 (m, 1H), 7.37-7.28 (m, 2H),2.90-2.77 (m, 1H), 1.09 (d, J=6.8, 6H).

Example 200

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}acetamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-((2-bromophenyl)thio)acetamide. MS (ESI): mass calcd.for C₁₈H₁₅FN₄OS, 354.10; m/z found, 355.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.41-8.36 (dd, J=2.2, 1.4, 1H), 8.10-8.06 (d, J=1.5, 1H),7.93-7.87 (m, 1H), 7.53-7.48 (m, 1H), 7.39-7.34 (m, 1H), 7.33-7.25 (m,4H), 3.52 (s, 2H).

Example 201

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}-N,N-diethylacetamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-((2-bromophenyl)thio)-N,N-diethylacetamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄OS, 410.16; m/z found, 411.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.42-8.35 (d, J=1.9, 1H), 8.12-8.06 (d, J=1.5, 1H),7.94-7.86 (m, 1H), 7.63-7.55 (dd, J=7.1, 2.1, 1H), 7.41-7.23 (m, 5H),3.62 (s, 2H), 3.31-3.26 (m, 4H), 1.13-1.08 (t, J=7.1, 3H), 1.07-1.03 (t,J=7.1, 3H).

Example 202

5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfanyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-((2-bromophenyl)thio)-1-morpholinoethanone. MS (ESI):mass calcd. for C₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.41-8.39 (m, 1H), 8.10-8.08 (d, J=1.5, 1H),7.95-7.89 (m, 1H), 7.68-7.61 (m, 1H), 7.41-7.34 (m, 2H), 7.34-7.29 (m,2H), 7.29-7.25 (dd, J=12.2, 1.7, 1H), 3.66 (s, 2H), 3.58-3.53 (t, J=4.9,2H), 3.54-3.49 (t, J=4.8, 2H), 3.49-3.44 (m, 2H), 3.40-3.35 (t, J=4.8,2H).

Example 203

racemic5-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}methyl)-1,3-oxazolidin-2-one

The title compound was prepared in a manner similar to that described inExample 88 using racemic5-(((2-bromophenyl)thio)methyl)oxazolidin-2-one. MS (ESI): mass calcd.for C₂₀H₁₇FN₄O₂S, 396.11; m/z found, 397.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.41-8.37 (m, 1H), 8.09-8.07 (d, J=1.5, 1H), 7.94-7.88 (m, 1H),7.65-7.59 (m, 1H), 7.43-7.37 (m, 1H), 7.37-7.29 (m, 3H), 7.28-7.23 (dd,J=12.2, 1.7, 1H), 4.68-4.54 (m, 1H), 3.56-3.48 (t, J=8.8, 1H), 3.29-3.22(dd, J=9.2, 6.4, 1H), 3.20-3.13 (m, 1H), 3.07-3.01 (m, 1H).

Example 204

N-(2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}ethyl)benzamide

The title compound was prepared in a manner similar to that described inExample 88 using N-(2-((2-bromophenyl)thio)ethyl)benzamide. MS (ESI):mass calcd. for C₂₅H₂₁FN₄OS, 444.14; m/z found, 445.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.38-8.32 (m, 1H), 8.09-8.03 (d, J=1.4, 1H),7.89-7.83 (t, J=8.1, 1H), 7.73-7.67 (m, 2H), 7.67-7.63 (d, J=7.9, 1H),7.52-7.45 (m, 1H), 7.44-7.34 (m, 3H), 7.30-7.26 (m, 3H), 7.26-7.21 (dd,J=12.4, 1.7, 1H), 3.53-3.46 (t, J=7.0, 2H), 3.11-3.03 (t, J=7.0, 2H).

Example 205

5-(3-Fluoro-2′-{[4-(methylsulfonyl)benzyl]sulfanyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (2-bromophenyl)(4-(methylsulfonyl)benzyl)sulfane. MS(ESI): mass calcd. for C₂₄H₂₀FN₃O₂S₂, 465.10; m/z found, 466.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.41-8.35 (m, 1H), 8.12-8.04 (d, J=1.5, 1H),7.87-7.81 (m, 1H), 7.79-7.73 (m, 2H), 7.59-7.48 (m, 1H), 7.39-7.30 (m,4H), 7.29-7.24 (m, 1H), 7.18-7.12 (dd, J=8.0, 1.7, 1H), 7.11-7.03 (dd,J=12.3, 1.7, 1H), 4.04 (s, 2H), 3.08 (s, 3H).

Example 206

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-5-(trifluoromethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₇H₁₂F₄N₄O₂S, 412.06; m/z found, 413.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.41 (s, 1H), 8.38 (s, 1H), 8.22-8.16 (m, 1H),8.01-7.92 (m, 2H), 7.63-7.58 (d, J=8.0, 1H), 7.40-7.30 (m, 2H).

Example 207

5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 1-bromo-2-(methylsulfonyl)-4-(trifluoromethyl)benzeneand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₃F₄N₃O₂S, 411.07; m/z found, 412.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.45-8.44 (d, J=2.0, 1H), 8.43 (s,1H), 8.10-8.09 (d, J=1.5, 1H), 8.09-8.06 (dd, J=7.8, 1.7, 1H), 8.02-7.97(m, 1H), 7.71-7.68 (d, J=7.9, 1H), 7.41-7.39 (m, 1H), 7.39-7.37 (m, 1H),2.88 (s, 3H).

Example 208

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-methyl-5-(trifluoromethyl)benzenesulfonamide.MS (ESI): mass calcd. for C₁₈H₁₄F₄N₄O₂S, 426.08; m/z found, 427.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.43-8.36 (m, 1H), 8.34-8.27 (d,J=1.9, 1H), 8.21-8.14 (d, J=1.4, 1H), 8.02-7.92 (m, 2H), 7.66-7.61 (d,J=7.9, 1H), 7.35 (s, 1H), 7.34-7.32 (dd, J=4.3, 1.6, 1H), 2.46 (s, 3H).

Example 209

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one

The title compound was prepared in a manner similar to that described inExample 88 using4-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-2-one. MS(ESI): mass calcd. for C₂₁H₁₇F₄N₅O₃S, 495.10; m/z found, 496.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.43-8.37 (m, 2H), 8.24-8.21 (d, J=1.4, 1H),8.08-8.04 (dd, J=8.0, 1.8, 1H), 8.04-7.99 (m, 1H), 7.69-7.65 (d, J=7.9,1H), 7.38-7.35 (m, 1H), 7.35-7.32 (dd, J=5.8, 1.6, 1H), 3.38 (s, 2H),3.15 (s, 4H).

Example 210

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₉H₁₆F₄N₄O₃S, 456.09; m/z found, 457.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.41-8.39 (m, 1H), 8.36 (s, 1H), 8.16-8.13 (d,J=1.5, 1H), 7.99-7.93 (m, 2H), 7.64-7.61 (d, J=8.0, 1H), 7.38-7.36 (m,1H), 7.36-7.33 (dd, J=5.0, 1.6, 1H), 3.49-3.45 (t, J=5.9, 2H), 2.93-2.86(t, J=5.8, 2H).

Example 211

4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide.MS (ESI): mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.34-8.31 (m, 1H),8.20-8.16 (d, J=1.5, 1H), 8.01-7.94 (m, 2H), 7.65-7.59 (d, J=7.9, 1H),7.37-7.34 (m, 1H), 7.34-7.31 (dd, J=2.9, 1.5, 1H), 2.88-2.76 (q, J=7.2,2H), 1.07-0.94 (t, J=7.2, 3H).

Example 212

5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide.MS (ESI): mass calcd. for C₂₂H₂₁F₄N₅O₂S, 495.14; m/z found, 496.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.44-8.41 (m, 1H), 8.41-8.38 (d,J=2.0, 1H), 8.13-8.10 (d, J=1.5, 1H), 8.10-8.06 (m, 1H), 8.05-7.97 (m,1H), 7.73-7.60 (d, J=8.0, 1H), 7.39-7.37 (dd, J=6.6, 1.6, 1H), 7.37-7.35(dd, J=2.8, 1.7, 1H), 2.85 (s, 3H), 3.93-2.45 (br m, 8H).

Example 213

5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride Step A: Ethyl 3-(2-bromophenylthio)propanoate

A mixture of 2-bromobenzenethiol (6 g, 30 mmol), ethyl3-chloropropanoate (13 g, 96 mmol), K₂CO₃ (8.8 g, 64 mmol) and acetone(150 mL) was refluxed for 15 h. The reaction mixture was filtered andthe filter cake washed with acetone (50 mL). The filtrate wasconcentrated to dryness and subjected to FCC to give ethyl3-(2-bromophenylthio)propanoate (7 g, 78%). MS (ESI): mass calcd. forC₁₁H₁₃O₂S, 287.98; m/z found, 288.8 [M+H]⁺.

Step B: Ethyl3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate

A mixture of ethyl 3-(2-bromophenylthio)propanoate (7 g, 24 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(7.6 g, 24 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (378 mg, 0.52 mmol) and Na₂CO₃ (5g, 48 mmol) in dioxane/water (20 mL/5 mL) was stirred at 80° Celsius for5 hours under N₂, then poured into water (60 mL) and extracted withEtOAc (50 mL×3). The combined organic extracts were dried over Na₂SO₄,filtered, concentrated to dryness and purified by FCC to give ethyl3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (7.7g, 80%) as a white solid. MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₂S,397.13; m/z found, 397.9 [M+H]⁺.

Step C: 4′-(5-Aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol

To a solution consisting of ethyl3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (7.7g, 19.4 mmol) and THF (60 mL) was added t-BuOK (4.3 g, 38.8 mmol) andthe mixture stirred for 1 hour at rt. The reaction mixture was pouredinto water (100 mL) and the system brought to a pH=5-6 with 1 M HCl. Themixture was, extracted with EtOAc (80 mL×3) and the combined extractsdried over Na₂SO₄, filtered and concentrated to dryness to give4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol (4.6 g, 80%). MS(ESI): mass calcd. for C₁₆H₁₂FN₃S, 297.07; m/z found, 298.0 [M+H]⁺.

Step D

To a solution of 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol (400mg, 1.34 mmol) and 2-chloropyrimidine (167 mg, 1.47 mmol) in DMF (8 mL)were added DIPEA (345 mg, 2.68 mmol) and Ph₃P (351 mg, 1.34 mmol) andthe resultant mixture heated at 80° Celsius for 1 hour under a N₂atmosphere for 15 h. The mixture was cooled to rt, concentrated todryness and the residue subjected to FCC to give the title compound (350mg, 68%). MS (ESI): mass calcd. for C₂₀H₁₄FN₅S.HCl, 375.10; m/z found,376.0 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.42 (d, J=4.9, 2H), 8.33-8.28(m, 1H), 8.03 (d, J=1.4, 1H), 7.79-7.69 (m, 2H), 7.60-7.53 (m, 1H),7.51-7.43 (m, 2H), 7.21 (dd, J=8.0, 1.7, 1H), 7.15 (dd, J=12.3, 1.6,1H), 7.06 (m, 1H).

Example 214

5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₄FN₅S, 375.10; m/zfound, 375.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (d, J=1.1, 1H), 8.46(d, J=1.4, 2H), 8.44 (d, J=5.6, 1H), 7.81-7.75 (m, 1H), 7.73-7.65 (m,1H), 7.62-7.51 (m, 3H), 7.30 (dd, J=11.8, 1.6, 1H), 7.24 (dd, J=7.9,1.7, 1H), 6.96 (dd, J=5.6, 1.3, 1H), 6.90 (s, 2H).

Example 215

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.25 (m,3H), 7.94 (m 1H), 7.82 (d, J=7.4, 1H), 7.74 (m, 1H), 7.67-7.58 (m, 2H),7.34-7.23 (m, 2H), 5.94 (s, 1H).

Example 216

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 390.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (m, 1H),8.16 (s, 1H), 7.88 (m, 1H), 7.83-7.75 (m, 2H), 7.71-7.63 (m, 1H),7.58-7.52 (m, 2H), 7.32-7.21 (m, 2H), 6.37 (d, J=7.2, 1H).

Example 217

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and5-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 391.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.30(m, 1H), 8.22 (s, 1H), 8.02 (d, J=1.4, 1H), 7.90 (s, 1H), 7.80 (m, 1H),7.59-7.54 (m, 2H), 7.52-7.44 (m, 2H), 7.24 (dd, J=6.5, 1.6, 1H), 7.21(m, 1H).

Example 218

5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and2-chloropyrazine. MS (ESI): mass calcd. for C₂₀H₁₄FN₅S, 375.10; m/zfound, 375.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26-8.24 (m, 3H), 8.18(d, J=2.6, 1H), 8.08 (d, J=1.4, 1H), 7.84 (m, 1H), 7.77-7.69 (m, 1H),7.64-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.27-7.14 (m, 2H).

Example 219

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and5-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H),8.24 (s, 1H), 7.95 (s, 2H), 7.88 (m, 1H), 7.65-7.59 (m, 1H), 7.53-7.38(m, 3H), 7.27-7.16 (m, 2H).

Example 220

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonamideformic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)-N-methylmethanesulfonamide. MS (ESI): mass calcd.for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.34 (s, 1H), 8.25 (s, 1H), 7.99 (m, 1H), 7.68-7.60 (m, 1H),7.50-7.40 (m, 2H), 7.39-7.31 (m, 3H), 4.36 (s, 2H), 2.49 (s, 3H).

Example 221

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(2-hydroxyethyl)methanesulfonamideformic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)-N-(2-hydroxyethyl)methanesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.0 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.38 (d, J=1.2, 1H), 8.31 (s, 1H), 8.02 (m, 1H),7.70-7.63 (m, 1H), 7.49-7.40 (m, 2H), 7.40-7.30 (m, 3H), 4.40 (s, 2H),3.51 (t, J=5.9, 2H), 2.95 (t, J=5.9, 2H), 2.66 (s, 1H).

Example 222

1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)azetidin-3-olformic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-((2-bromobenzyl)sulfonyl)azetidin-3-ol. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₃S, 414.12; m/z found, 414.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.43-8.38 (m, 1H), 8.08 (d, J=1.5, 1H), 7.95 (m, 1H), 7.68-7.60 (m, 1H),7.49-7.41 (m, 2H), 7.39-7.28 (m, 3H), 4.45-4.36 (m, 3H), 3.79-3.70 (m,2H), 3.67-3.59 (m, 2H).

Example 223

4-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperazin-2-oneformic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 4-((2-bromobenzyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd.for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 441.9 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.41 (s, 1H), 8.08 (d, J=1.3, 1H), 7.96 (m, 1H), 7.70-7.62 (m,1H), 7.52-7.28 (m, 5H), 4.48 (s, 2H), 3.63 (s, 2H), 3.25 (s, 4H).

Example 224

(S)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)-methanesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand(S)-1-(2-bromophenyl)-N-(1-hydroxypropan-2-yl)methanesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 416.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.43-8.36 (m, 1H), 8.03 (d, J=1.5, 1H), 7.92(m, 1H), 7.70-7.59 (m, 1H), 7.47-7.28 (m, 5H), 7.12 (d, J=6.6, 1H), 6.71(s, 2H), 4.75 (t, J=5.4, 1H), 4.35 (q, J=14.1, 2H), 3.31-3.11 (m, 3H),1.01 (d, J=6.2, 3H).

Example 225

(R)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)-methanesulfonamidehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand (R)-1-(2-bromophenyl)-N-(1-hydroxypropan-2-yl)methanesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₃S, 416.48; m/z found, 417.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.32 (d, J=3.7, 2H), 7.99 (m, 1H), 7.77-7.66 (m,1H), 7.50-7.39 (m, 2H), 7.39-7.28 (m, 3H), 4.41 (q, J=13.9, 2H),3.49-3.33 (m, 3H), 1.11 (d, J=6.3, 3H).

Example 226

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(trans-4-hydroxycyclohexyl)-methanesulfonamideformic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineandtrans-1-(2-bromophenyl)-N-((trans)-4-hydroxycyclohexyl)-methane-sulfonamide.MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₃S.HCO₂H, 456.16; m/z found, 457.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.08 (d, J=1.3, 1H),7.94 (m, 1H), 7.72-7.63 (m, 1H), 7.47-7.38 (m, 1H), 7.38-7.27 (m, 3H),4.36 (s, 2H), 3.42 (s, 1H), 2.97 (s, 1H), 1.84 (d, J=9.0, 4H), 1.38-1.10(m, 4H).

Example 227

(S)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]-methanesulfonamidehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (S)-1-(2-bromophenyl)-N-(2-hydroxypropyl)-methane-sulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.28-8.23 (m, 1H), 8.13 (m, 1H),7.70-7.62 (m, 1H), 7.49-7.30 (m, 5H), 4.40 (s, 2H), 3.77-3.65 (m, 1H),2.80 (d, J=5.9, 2H), 1.09 (d, J=6.3, 3H).

Example 228

(R)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2R)-2-hydroxypropyl]-methanesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand (R)-1-(2-bromophenyl)-N-(2-hydroxypropyl)methane-sulfonamide.

Example 229

5-(2′-{[(4-Aminopiperidin-1-yl)sulfonyl]methyl}-3-fluorobiphenyl-4-yl)pyrazin-2-aminehydrochloride Step A: tert-Butyl1-((4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylsulfonyl)-piperidin-4-ylcarbamate

A mixture of tert-butyl(1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.46mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(175 mg, 0.55 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (34 mg, 0.046 mmol) and Na₂CO₃(150 mg, 1.36 mmol) in dry DMF (15 mL) was stirred at 130° Celsius underN₂. After 5 hours, the solvent was removed under vacuum and the residuewas subjected to FCC purification to give tert-butyl1-((4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylsulfonyl)piperidin-4-ylcarbamate(190 mg, 76%). MS (ESI): mass calcd. for C₂₇H₃₂FN₅O₂S, 541.22; m/zfound, 542.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.03 (s,1H), 7.95 (s, 1H), 7.78-7.29 (m, 7H), 6.87 (d, J=5.2, 1H), 6.73 (s, 2H),4.34 (s, 2H), 3.45-3.33 (m, 3H), 2.85-2.75 (m, 2H), 1.72 (d, J=12.4,2H), 1.45-1.30 (m, 11H).

Step B

A mixture of tert-butyl1-((4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylsulfonyl)piperidin-4-ylcarbamate(190 mg, 0.35 mmol) in HCl (20 mL, 6 N in methanol) was stirred at rtfor 24 hours. The solvent was removed under reduced pressure and theresidue purified by HPLC to give the title compound (80 mg HCl salt,61%). MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.10 (br, 4H), 7.95(m, 1H), 7.64-7.55 (m, 1H), 7.52-7.32 (m, 4H), 4.80 (br, 4H), 4.37 (s,2H), 3.50 (d, J=13.0, 2H), 3.10 (s, 1H), 2.76 (t, J=12.6, 2H), 1.91 (d,J=11.0, 3H), 1.58-1.41 (m, 2H).

Example 230

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamidehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand (2-bromophenyl)methanesulfonamide. MS (ESI): mass calcd. forC₁₇H₁₅FN₄O₂S, 358.09; m/z found, 359.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.36 (s, 1H), 8.12 (s, 1H), 7.92 (m, 1H), 7.66-7.56 (m, 1H), 7.38 (m,5H), 6.98 (s, 2H), 4.31 (s, 2H).

Example 231

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamideformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)-N-ethylmethanesulfonamide. MS (ESI): mass calcd.for C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.39 (s, 1H), 8.08 (d, J=1.4, 1H), 7.93 (m, 1H), 7.71-7.61 (m,1H), 7.49-7.27 (m, 5H), 4.36 (s, 2H), 2.85 (q, J=7.2, 2H), 1.06 (t,J=7.2, 3H).

Example 232

1-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]ureahydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)urea. MS (ESI): masscalcd. for C₂₃H₂₅FN₆O₃S, 484.17; m/z found, 485.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) 8.37 (s, 1H), 8.16 (s, 1H), 7.96 (t, J=8.2, 1H), 7.66-7.28(m, 6H), 4.35 (s, 2H), 3.41-3.32 (m, 2H), 2.85-2.70 (m, 2H), 1.83-1.70(m, 2H), 1.33-1.19 (m, 2H).

Example 233

N-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]-acetamideformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand N-(1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)acetamide. MS (ESI):mass calcd. for C₂₄H₂₆FN₅O₃S, 483.17; m/z found, 484.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.03 (d, J=1.3, 1H), 7.95 (m, 1H),7.81 (d, J=7.3, 1H), 7.64-7.55 (m, 1H), 7.50-7.31 (m, 5H), 6.73 (s, 2H),4.35 (s, 2H), 3.71-3.56 (m, 1H), 3.39 (d, J=11.6, 2H), 2.79 (t, J=10.8,2H), 1.82-1.67 (m, 5H), 1.41-1.24 (m, 3H).

Example 234

5-{2′-[(Ethylsulfanyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amineformic acid salt Step A:(4′-(5-Aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methanol

A mixture of 2-(hydroxymethyl)phenylboronic acid (1 g, 7 mmol),5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (1.76 g, 6.6 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (483 mg, 0.66 mmol) and Na₂CO₃ (2.1 g, 20 mmol) inDMF (50 mL) was stirred at 110° Celsius overnight under N₂. The solutionwas concentrated to dryness and the residue purified by FCC to give(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methanol (1.2 g, 62%).¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.02 (d, J=1.4, 1H), 7.90 (m,1H), 7.57 (d, J=7.4, 1H), 7.49-7.26 (m, 5H), 6.69 (s, 2H), 5.20 (t,J=5.3, 1H), 4.44 (d, J=5.3, 2H).

Step B: 5-(6′-(Chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine

A mixture of (4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methanol(1.8 g, 6.1 mmol) and SOCl₂ (6 mL) in DCM (20 mL) was stirred at 70°Celsius for 4 hours. The reaction mixture was cooled to rt andconcentrated to dryness to give5-(6′-(chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine (1.86 g,98%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.96 (m,1H), 7.66-7.57 (m, 1H), 7.51-7.42 (m, 2H), 7.40-7.30 (m, 3H), 6.89-6.62(br s, 2H), 4.73 (s, 2H).

Step C: S-(4′-(5-Aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylethanethioate

A mixture of 5-(6′-(chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine(1.86 g, 5.94 mmol) and KSAc (0.81 g, 7.1 mmol) in 1,4-dioxane/H₂O (30mL/6 mL) was stirred at rt for 2 hours. Then the solvent was removedunder vacuum and the residue purified by FCC to giveS-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate(1.42 g, 68%). MS (ESI): mass calcd. for C₁₉H₁₈FN₃OS, 353.10; m/z found,353.9 [M+H]⁺.

Step D

To a solution ofS-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate(100 mg, 0.28 mmol) in CH₃OH (30 mL) were added Ph₃P (147 mg, 0.56 mmol)and K₂CO₃ (78 mg, 0.56 mmol) followed by drop-wise addition ofbromoethane (60 mg, 0.56 mmol). After 16 hours, the mixture wasconcentrated to dryness and the residue was purified by prep-TLC andfollowed by HPLC to give the title compound (70 mg HCOOH salt, 73%). MS(ESI): mass calcd. for C₁₉H₁₈FN₃S, 339.12; m/z found, 340.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.38 (m, 1H), 8.07 (d, J=1.5, 1H), 7.89 (m, 1H),7.48-7.40 (m, 1H), 7.37-7.21 (m, 5H), 3.71 (s, 2H), 2.42 (q, J=7.4, 2H),1.13 (t, J=7.4, 3H).

Example 235

5-{3-Fluoro-2′-[(methylsulfanyl)methyl]biphenyl-4-yl}pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 234 utilizing iodomethane. MS (ESI): mass calcd.for C₁₈H₁₆FN₃S, 325.10; m/z found, 326.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.45 (s, 1H), 8.30 (d, J=1.0, 1H), 8.04 (m, 1H), 7.49-7.24 (m, 6H),3.68 (s, 2H). The title

Example 236

5-(3-Fluoro-2′-{[(1-methylethyl)sulfanyl]methyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 234 utilizing 2-iodopropane. MS (ESI): mass calcd.for C₂₀H₂₀FN₃S, 353.14; m/z found, 354.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.66 (s, 1H), 8.23 (d, J=1.2, 1H), 8.12 (m, 1H), 7.48-7.23 (m, 6H),3.73 (s, 2H), 2.84-2.71 (m, 1H), 1.16 (d, J=6.7, 6H).

Example 237

2-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 234 utilizing 4-amino-2-chloropyrimidine. MS (ESI):mass calcd. for C₁₈H₁₆FN₃S, 404.12; m/z found, 404.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.77-8.68 (m, 1H), 8.21 (d, J=1.3, 1H), 8.10 (m, 1H), 7.79(d, J=6.9, 1H), 7.63-7.55 (m, 1H), 7.45-7.22 (m, 5H), 6.73 (d, J=6.8,1H), 4.57 (s, 2H).

Example 238

6-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 4-amino-6-chloropyrimidine. MS (ESI):mass calcd. for C₂₁H₁₇FN₆S, 404.12; m/z found, 405.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.78-8.68 (m, 1H), 8.38 (d, J=0.6, 1H), 8.26 (d, J=1.3,1H), 8.16 (m, 1H), 7.66-7.57 (m, 1H), 7.50-7.44 (m, 2H), 7.42-7.31 (m,3H), 6.58 (d, J=3.4, 1H), 4.51 (s, 2H).

Example 239

5-(3-Fluoro-2′-((pyridazin-3-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 3-chloropyrazine. MS (ESI): mass calcd.for C₂₁H₁₆FN₅S, 389.11; m/z found, 390.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 9.33-9.24 (m, 1H), 8.74 (s, 1H), 8.31-8.20 (m, 2H), 8.14 (m, 2H),7.72-7.64 (m, 1H), 7.50-7.33 (m, 5H), 4.63 (s, 2H).

Example 240

6-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyridazin-3-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 3-chloropyrazine. MS (ESI): mass calcd.for C₂₁H₁₇FN₆S, 404.12; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.70-8.63 (m, 1H), 8.28 (d, J=1.1, 1H), 8.12 (m, 1H), 7.65-7.57 (m,2H), 7.46-7.41 (m, 2H), 7.39 (dd, J=8.1, 1.6, 1H), 7.36-7.30 (m, 3H),4.43 (s, 2H).

Example 241

5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 4-((2-bromophenyl)sulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide. MS(ESI): mass calcd. for C₂₁H₂₀FN₃O₄S₂, 461.09; m/z found, 462.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.07-8.04 (m, 2H), 7.92 (m,1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.49 (dd, J=7.5, 1.0, 1H), 7.38-7.31(m, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.74 (s, 2H), 3.25-3.06 (m, 5H),2.16-2.04 (m, 2H), 2.02-1.86 (m, 2H).

Example 242

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 234 utilizing 2-amino-4-chloropyrimidine. MS (ESI):mass calcd. for C₂₀H₁₅FN₆S, 390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.39-8.32 (m, 1H), 8.01 (d, J=1.5, 1H), 7.94 (d, J=6.1,1H), 7.85 (m, 1H), 7.76 (d, J=7.8, 1H), 7.71-7.65 (m, 1H), 7.62-7.53 (m,2H), 7.35-7.24 (m, 2H), 6.88 (s, 2H), 6.18 (d, J=6.4, 1H).

Example 243

5-(3-Fluoro-2′-((pyrimidin-4-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 4-chloropyrimidine. MS (ESI): masscalcd. for C₁₈H₁₆FN₃S, 389.11; m/z found, 390.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.70 (d, J=1.4, 1H), 8.53 (d, J=4.9, 2H), 8.20 (d, J=1.3, 1H),8.10 (m, 1H), 7.65-7.55 (m, 1H), 7.39-7.25 (m, 5H), 7.13 (m, 1H), 4.46(s, 2H).

Example 244

5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-pyrazin-2-amineand (2-(((2-bromophenyl)thio)methoxy)ethyl)trimethylsilane. MS (ESI):mass calcd. for C₂₂H₂₆FN₃OSSi, 427.16; m/z found, 428.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.43-8.36 (m, 1H), 8.07 (d, J=1.5, 1H), 7.89 (m, 1H),7.73 (dd, J=6.7, 1.4, 1H), 7.40-7.17 (m, 5H), 4.90 (s, 2H), 3.64-3.50(m, 2H), 0.91-0.78 (m, 2H), 0.04 (s, 9H).

Example 245

5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 244 utilizing5-[3-fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)-biphenyl-4-yl]-pyrazin-2-amine.MS (ESI): mass calcd. for C₂₂H₂₆FN₃O₃SSi, 459.14; m/z found, 459.9[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.44-8.39 (m, 1H), 8.18 (dd, J=8.0,1.3, 1H), 8.08 (d, J=1.4, 1H), 7.94 (m, 1H), 7.80-7.75 (m, 1H),7.72-7.65 (m, 1H), 7.47 (dd, J=7.5, 1.4, 1H), 7.31 (dd, J=3.6, 1.7, 1H),7.28 (dd, J=7.7, 1.5, 1H), 4.34 (s, 2H), 3.77-3.68 (m, 2H), 0.85-0.75(m, 2H), 0.08 (s, 9H).

Example 246

5-(3-Fluoro-2′-{[3-(methylsulfonyl)propyl]sulfonyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 1-bromo-2-((3-(methylsulfonyl)propyl)sulfonyl)benzene. MS (ESI):mass calcd. for C₂₀H₂₀FN₃O₄S₂, 449.53; m/z found, 450.0 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.69 (d, J=1.3, 1H), 8.25 (d, J=1.3, 1H), 8.18 (dd,J=7.9, 1.3, 1H), 8.12 (m, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.48 (dd,J=7.4, 1.3, 1H), 7.44-7.34 (m, 2H), 3.20-3.09 (m, 4H), 2.89 (s, 3H),2.12-1.96 (m, 2H).

Example 247

5-(3-Fluoro-2′-{[(2R)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amineStep A: (R)-tert-Butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (R)-tert-butyl4-((2-bromophenyl)sulfonyl)-3-methypiperazine-1-carboxylate. MS (ESI):mass calcd. for C₂₆H₃₀FN₅O₄S, 527.20; m/z found, 528.2 [M+H]⁺.

Step B

The title compound was prepared by dissolving (R)-tert-butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate(42 mg, 0.08 mmol) in a 50/50 mixture of DCM/TFA (1 mL) and allowing itto stir at rt for 2 h. The reaction mixture was concentrated to drynessand the residue subjected to HPLC purification to give the titlecompound (29 mg, 85%). MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15;m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H),8.16 (dd, J=8.0, 1.4, 1H), 7.65-7.58 (m, 1H), 7.56-7.49 (m, 1H),7.48-7.39 (m, 1H), 7.38-7.31 (m, 3H), 5.18 (s, 2H), 3.64-3.52 (m, 1H),2.99-2.87 (m, 2H), 2.81-2.69 (m, 1H), 2.61-2.41 (m, 4H), 1.18 (d, J=6.8,3H).

Example 248

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-phenyl)pyrimidin-2-amineand (S)-2-bromo-N-(1-hydroxybutan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.47 (d, J=1.3, 2H), 8.18 (dd, J=7.9, 1.4, 1H),7.67-7.57 (m, 1H), 7.59-7.49 (m, 1H), 7.42-7.30 (m, 4H), 5.39 (s, 2H),5.07 (d, J=8.0, 1H), 3.55-3.38 (m, 2H), 3.25-3.11 (m, 1H), 1.93 (s, 1H),1.54-1.29 (m, 2H), 0.80 (t, J=7.4, 3H).

Example 249

4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phenyl)pyrimidin-2-amineand 2-bromo-N-(2-cyanoethyl)-N-cyclopropylbenzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₀FN₅O₂S, 437.13; m/z found, 438.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.57 (d, J=1.4, 2H), 8.17 (dd, J=7.9, 1.3, 1H),7.71-7.62 (m, 1H), 7.62-7.52 (m, 1H), 7.49-7.40 (m, 1H), 7.33 (dd,J=7.5, 1.4, 1H), 7.20 (dd, J=8.0, 1.7, 1H), 7.14 (dd, J=11.1, 1.7, 1H),5.20 (s, 2H), 3.02 (t, J=7.0, 2H), 2.59-2.41 (m, 3H), 0.65-0.55 (m, 2H),0.39-0.28 (m, 2H).

Example 250

4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phenyl)pyrimidin-2-amineand 2-bromo-N-(2-cyanoethyl)benzenesulfonamide. MS (ESI): mass calcd.for C₁₉H₁₆FN₅O₂S, 397.10; m/z found, 398.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.50 (d, J=1.4, 2H), 8.18 (dd, J=7.9, 1.4, 1H), 7.70-7.64 (m,1H), 7.62-7.55 (m, 1H), 7.49-7.42 (m, 1H), 7.40-7.32 (m, 3H), 5.36 (s,2H), 5.24 (t, J=6.5, 1H), 3.07 (m, 2H), 2.50 (t, J=6.5, 2H).

Example 251

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phenyl)pyrimidin-2-amineand 2-bromo-N-(3-hydroxy-2,2-dimethylpropyl)-benzenesulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.53 (d, J=1.4, 2H), 8.12 (dd, J=7.8, 1.5, 1H),7.62-7.55 (m, 1H), 7.55-7.48 (m, 1H), 7.48-7.38 (m, 1H), 7.38-7.27 (m,3H), 5.08 (s, 2H), 4.23 (t, J=6.6, 1H), 3.33-3.21 (m, 2H), 2.61 (d,J=6.8, 2H), 1.40 (s, 6H).

Example 252

racemic(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phenyl)pyrimidin-2-amineand racemic (4-((2-bromophenyl)sulfonyl)morpholin-2-yl)methanol. MS(ESI): mass calcd. for C₂₁H₂₁FN₄O₄S, 444.13; m/z found, 445.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.10 (dd, J=7.9, 1.4, 1H),7.70-7.60 (m, 1H), 7.60-7.52 (m, 1H), 7.47-7.35 (m, 2H), 7.33-7.26 (m,2H), 5.22 (s, 2H), 3.86-3.76 (m, 1H), 3.63-3.51 (m, 1H), 3.51-3.29 (m,3H), 3.24-3.09 (m, 2H), 2.64-2.52 (m, 1H), 2.45 (dd, J=12.4, 10.5, 1H),1.95 (s, 1H).

Example 253

5-(3-Fluoro-2′-{[(2S)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amineStep A: (S)-tert-Butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (S)-tert-butyl4-((2-bromophenyl)sulfonyl)-3-methylpiperazine-1-carboxylate. MS (ESI):mass calcd. for C₂₆H₃₀FN₅O₄S, 527.20; m/z found, 528.2 [M+H]⁺.

Step B

The title compound was prepared as described in the preparation ofExample 252 using (S)-tert-butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate.MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₂S, 427.15; m/z found, 428.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.16 (dd, J=7.9, 1.3,1H), 7.65-7.58 (m, 1H), 7.56-7.49 (m, 1H), 7.48-7.39 (m, 1H), 7.38-7.31(m, 3H), 5.16 (s, 2H), 3.64-3.51 (m, 1H), 3.02-2.86 (m, 2H), 2.81-2.70(m, 1H), 2.63-2.41 (m, 4H), 1.18 (d, J=6.8, 3H).

Example 254

5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₉H₁₆FN₃O₂S, 369.10; m/z found, 370.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.59 (d, J=1.5, 2H), 8.14 (dd, J=7.9, 1.5, 1H), 7.70-7.63 (m, 1H),7.62-7.54 (m, 1H), 7.45 (m, 1H), 7.41-7.28 (m, 3H), 5.23 (s, 2H),2.19-2.06 (m, 1H), 1.16-1.07 (m, 2H), 0.93-0.81 (m, 2H).

Example 255

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-bromo-N-(1,3-dihydroxy-2-methylpropan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₄S, 432.13; m/z found, 433.1 [M+H]⁺.

Example 256

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3S)-piperidin-3-yl]biphenyl-2-sulfonamideStep A: (S)-tert-Butyl3-(4′-2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-ylsulfonamido)piperidine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (S)-tert-butyl3-(2-bromo-N-methylphenylsulfonamido)-piperidine-1-carboxylate yielding41 mg (48%) of the title compound after HPLC purification. MS (ESI):mass calcd. for C₂₇H₃₂FN₅O₄S, 541.21; m/z found, 542.1 [M+H]⁺.

Step B

The title compound was prepared as described in the preparation ofExample 247 using (S)-tert-butyl3-(4′-2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-ylsulfonamido)piperidine-1-carboxylate.The crude product was purified by HPLC to give the title compound (35mg, 91%). MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found,442.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.14 (dd,J=7.9, 1.4, 1H), 7.65-7.57 (m, 1H), 7.56-7.49 (m, 1H), 7.48-7.38 (m,1H), 7.37-7.24 (m, 3H), 5.19 (s, 2H), 3.43-3.24 (m, 1H), 2.96-2.74 (m,2H), 2.51 (t, J=11.3, 1H), 2.42 (s, 4H), 2.38-2.27 (m, 1H), 1.78-1.21(m, 4H).

Example 257

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3R)-piperidin-3-yl]biphenyl-2-sulfonamideStep A: R)-tert-Butyl3-(4′-2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-ylsulfonamido)piperidine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (R)-tert-butyl3-(2-bromo-N-methylphenylsulfonamido)piperidine-1-carboxylate. MS (ESI):mass calcd. for C₂₇H₃₂FN₅O₄S, 541.21; m/z found, 542.2 [M+H]⁺.

Step B

The title compound was prepared as described in the preparation ofExample 247 using (R)-tert-butyl3-(4′-2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-ylsulfonamido)piperidine-1-carboxylate.MS (ESI): mass calcd. for C₂₂H₂₄FN₅O₂S, 441.16; m/z found, 442.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.14 (dd, J=8.0, 1.4,1H), 7.65-7.57 (m, 1H), 7.56-7.49 (m, 1H), 7.47-7.36 (m, 1H), 7.37-7.25(m, 3H), 5.18 (s, 2H), 3.42-3.26 (m, 1H), 2.93-2.73 (m, 2H), 2.57-2.46(m, 1H), 2.42 (s, 3H), 2.38-2.27 (m, 2H), 1.73-1.23 (m, 4H).

Example 258

[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-yl]methanolStep A: (R)-tert-Butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-(hydroxymethyl)piperazine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (R)-tert-butyl4-((2-bromophenyl)sulfonyl)-3-hydroxymethy)piperazine-1-carboxylate. MS(ESI): mass calcd. for C₂₆H₃₀FN₅O₅S, 543.20; m/z found, 544.2 [M+H]⁺.

Step B

The title compound was prepared as described in the preparation ofExample 247 using (R)-tert-butyl4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-(hydroxymethyl)piperazine-1-carboxylate.MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃S, 443.14; m/z found, 444.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.18 (dd, J=8.0, 1.3,1H), 7.66-7.59 (m, 1H), 7.57-7.49 (m, 1H), 7.47-7.40 (m, 1H), 7.39-7.31(m, 3H), 5.19 (s, 2H), 3.94-3.77 (m, 2H), 3.52-3.39 (m, 1H), 3.34-3.18(m, 1H), 3.17-2.99 (m, 2H), 2.88-2.77 (m, 1H), 2.65-2.46 (m, 2H), 1.65(br s, 2H).

Example 259

racemic4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(cis)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand racemic 2-bromo-N-((cis)-2-hydroxycyclohexyl)-benzene-sulfonamide.MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.51 (d, J=1.3, 2H), 8.17 (dd, J=8.0, 1.4,1H), 7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.31 (m, 4H), 5.30 (s,2H), 4.83 (d, J=7.7, 1H), 3.78 (s, 1H), 3.20-3.11 (m, 1H), 1.72-1.65 (m,1H), 1.57-1.10 (m, 8H).

Example 260

racemic4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(trans)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-bromo-N-((trans)-2-hydroxycyclohexyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.51 (d, J=1.3, 2H), 8.17 (dd, J=8.0, 1.4, 1H),7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.31 (m, 4H), 5.30 (s, 2H),4.83 (d, J=7.7, 1H), 3.78 (s, 1H), 3.20-3.11 (m, 1H), 1.72-1.65 (m, 1H),1.57-1.10 (m, 8H).

Example 261

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-bromo-N-(2-hydroxyethyl)-N-isopropylbenzene-sulfonamide. MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.56 (d, J=1.4, 2H), 8.10 (dd, J=8.0, 1.4, 1H),7.65-7.57 (m, 1H), 7.58-7.49 (m, 1H), 7.49-7.38 (m, 1H), 7.37-7.28 (m,3H), 5.22 (s, 2H), 3.72 (p, J=6.7, 1H), 3.65-3.50 (m, 2H), 2.99 (t,J=6.0, 2H), 2.19 (d, J=7.0, 1H), 1.04 (d, J=6.7, 6H).

Example 262

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand trans-2-bromo-N-4-hydroxycyclohexyl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.22-8.15 (m, 1H), 7.67-7.60 (m, 1H),7.59-7.51 (m, 1H), 7.48-7.39 (m, 1H), 7.39-7.31 (m, 3H), 5.26 (s, 2H),4.11 (d, J=7.1, 1H), 3.60-3.43 (m, 1H), 3.10-2.94 (m, 1H), 1.93-1.73 (m,4H), 1.38 (d, J=4.4, 1H), 1.34-1.00 (m, 5H).

Example 263

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (S)-2-bromo-N-(2-oxopyrrolidin-3-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.51 (dd, J=2.2, 1.3, 2H), 8.18 (dd, J=7.9, 1.3, 1H),7.67-7.60 (m, 1H), 7.58-7.51 (m, 1H), 7.45-7.31 (m, 4H), 6.05 (d, J=9.3,1H), 5.51 (dd, J=9.8, 3.3, 1H), 5.35 (d, J=3.1, 2H), 3.67-3.55 (m, 1H),3.39-3.19 (m, 2H), 2.65-2.50 (m, 1H), 2.16-1.99 (m, 1H).

Example 264

5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminetrifluoroacetic salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₄S₂, 462.08; m/z found, 463.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.78 (d, J=0.9, 2H), 8.15 (dd, J=8.0, 1.1, 1H), 7.75(m, 1H), 7.71-7.62 (m, 2H), 7.44 (dd, J=7.6, 1.1, 1H), 7.40-7.31 (m,2H), 3.34 (dd, J=7.8, 3.2, 4H), 3.04-2.99 (m, 4H).

Example 265

1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-oltrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)azetidin-3-ol. MS (ESI): mass calcd. forC₁₉H₁₇FN₄O₃S, 400.10; m/z found, 401.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.79 (d, J=0.7, 2H), 8.08 (dd, J=8.0, 1.1, 1H), 7.72 (m, 1H), 7.68-7.55(m, 2H), 7.47-7.38 (m, 1H), 7.36 (dd, J=8.3, 1.5, 2H), 4.36 (m, 1H),3.76-3.64 (m, 2H), 3.60-3.53 (m, 2H).

Example 266

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3R)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(2-oxopiperidin-3-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 442.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.71 (d, J=0.7, 2H), 8.24 (dd, J=8.0, 1.2, 1H), 7.67(m, 1H), 7.58 (m, 2H), 7.42 (s, 1H), 7.41-7.39 (m, 1H), 7.38 (dd, J=7.6,1.2, 1H), 3.63 (dd, J=10.5, 5.8, 1H), 3.20 (dd, J=8.9, 5.1, 2H), 2.17(m, 1H), 1.89-1.80 (m, 1H), 1.78-1.64 (m, 2H).

Example 267

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(2-oxopiperidin-3-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 442.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.74 (d, J=0.8, 2H), 8.24 (dd, J=8.0, 1.1, 1H), 7.67(m, 1H), 7.62-7.54 (m, 2H), 7.42 (s, 1H), 7.42-7.40 (m, 1H), 7.38 (dd,J=7.6, 1.2, 1H), 3.64 (dd, J=10.5, 5.8, 1H), 3.20 (dd, J=8.7, 5.0, 2H),2.17 (m, 1H), 1.89-1.80 (m, 1H), 1.80-1.65 (m, 2H).

Example 268

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0 [M+H]⁺.¹H NMR (600 MHz, CD₃OD) δ 8.64 (d, J=0.9, 2H), 8.10 (dd, J=8.0, 1.1,1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.37 (dd, J=7.6, 1.2,1H), 7.33-7.24 (m, 2H), 3.86 (m, 1H), 1.22 (m, 3H).

Example 269

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzene-sulfonamide.MS (ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.2 [M+H]⁺.¹H NMR (600 MHz, CD₃OD) δ 8.68 (d, J=1.0, 2H), 8.15 (dd, J=8.0, 1.1,1H), 7.62 (m, 1H), 7.58-7.49 (m, 2H), 7.42-7.35 (m, 2H), 7.35-7.29 (m,1H), 3.50 (m, 2H), 3.06 (dd, J=5.8, 4.3, 1H), 0.84 (s, 9H).

Example 270

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzene-sulfonamide.MS (ESI): mass calcd. for C₂₂H₂₅FN₄O₃S, 444.16; m/z found, 445.2 [M+H]⁺.¹H NMR (600 MHz, CD₃OD) δ 8.69 (d, J=1.0, 2H), 8.15 (dd, J=8.0, 1.1,1H), 7.63 (m, 1H), 7.59-7.47 (m, 2H), 7.41-7.36 (m, 2H), 7.33 (m, 1H),3.50 (m, 2H), 3.06 (dd, J=5.9, 4.2, 1H), 0.84 (s, 9H).

Example 271

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(1-hydroxy-3-methylbutan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (600 MHz, CD₃OD) δ 8.71 (d, J=0.9, 2H), 8.15 (dd, J=8.0, 1.1, 1H),7.66-7.61 (m, 1H), 7.60-7.54 (m, 2H), 7.36 (m, 3H), 3.47-3.38 (m, 1H),3.38-3.32 (m, 1H), 3.06 (q, J=5.5, 1H), 1.84 (m, 1H), 0.83-0.78 (m, 6H).

Example 272

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.75 (d, J=1.0 Hz, 2H), 8.04 (dd, J=8.0, 1.3 Hz, 1H),7.70-7.65 (m, 1H), 7.64-7.58 (m, 2H), 7.41 (dd, J=7.6, 1.3 Hz, 1H),7.39-7.35 (m, 2H), 2.71 (s, 2H), 1.11 (s, 6H).

Example 273

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(1-hydroxy-3-methylbutan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹HNMR (600 MHz, CD₃OD) δ 8.71 (d, J=0.9, 2H), 8.15 (dd, J=8.0, 1.1, 1H),7.66-7.61 (m, 1H), 7.60-7.54 (m, 2H), 7.36 (m, 3H), 3.47-3.38 (m, 1H),3.38-3.32 (m, 1H), 3.06 (q, J=5.5, 1H), 1.84 (m, 1H), 0.83-0.78 (m, 6H).

Example 274

4′-(2-Aminopyrimidin-5-yl)-N-[(2S)-2,3-dihydroxypropyl]-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(2,3-dihydroxypropyl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₉FN₄O₄S, 418.11; m/z found, 419.1 [M+H]⁺.

Example 275

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide. MS (ESI): mass calcd.for C₁₈H₁₇FN₄O₃S, 388.10; m/z found, 389.1 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD) δ 8.75 (d, J=0.9, 2H), 8.07 (m, 1H), 7.71-7.66 (m, 1H), 7.63-7.59(m, 2H), 7.40 (dd, J=7.6, 1.1, 1H), 7.37 (m, 2H), 3.49 (t, J=5.9, 2H),2.90 (t, J=5.9, 2H).

Example 276

[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanoltrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol. MS (ESI):mass calcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.70 (d, J=1.0, 2H), 8.10 (dd, J=8.0, 1.2, 1H), 7.70(m, 1H), 7.64-7.61 (m, 1H), 7.59 (dd, J=10.9, 5.4, 1H), 7.41 (dd, J=7.6,1.2, 1H), 7.37-7.32 (m, 2H), 3.50 (m, 1H), 3.37 (dd, J=10.8, 3.9, 1H),3.21-3.15 (m, 1H), 3.03-2.95 (m, 2H), 1.88-1.75 (m, 3H), 1.73-1.66 (m,1H).

Example 277

[(2S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanoltrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-(1-((2-bromophenyl)sulfonyl)pyrrolidin-2-yl)methanol. MS (ESI):mass calcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.70 (d, J=1.0, 2H), 8.10 (dd, J=8.0, 1.2, 1H), 7.70(m, 1H), 7.64-7.61 (m, 1H), 7.59 (dd, J=10.9, 5.4, 1H), 7.41 (dd, J=7.6,1.2, 1H), 7.37-7.32 (m, 2H), 3.50 (m, 1H), 3.37 (dd, J=10.8, 3.9, 1H),3.21-3.15 (m, 1H), 3.03-2.95 (m, 2H), 1.88-1.75 (m, 3H), 1.73-1.66 (m,1H).

Example 278

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide-trifluoroaceticacid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): masscalcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.60 (d, J=1.2 Hz, 2H), 8.06 (dd, J=8.0, 1.3 Hz, 1H),7.71-7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.58-7.51 (m, 1H), 7.41 (dd,J=7.5, 1.4 Hz, 1H), 7.35 (s, 1H), 7.34-7.30 (m, 1H), 3.74-3.63 (m, 1H),2.76 (dd, J=13.1, 5.0 Hz, 1H), 2.69 (dd, J=13.0, 6.8 Hz, 1H), 1.06 (d,J=6.3 Hz, 3H).

Example 279

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): masscalcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.60 (d, J=1.2 Hz, 2H), 8.06 (dd, J=8.0, 1.3 Hz, 1H),7.71-7.65 (m, 1H), 7.63-7.58 (m, 1H), 7.58-7.51 (m, 1H), 7.41 (dd,J=7.5, 1.4 Hz, 1H), 7.35 (s, 1H), 7.34-7.30 (m, 1H), 3.74-3.63 (m, 1H),2.76 (dd, J=13.1, 5.0 Hz, 1H), 2.69 (dd, J=13.0, 6.8 Hz, 1H), 1.06 (d,J=6.3 Hz, 3H)

Example 280

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₃S, 416.13; m/z found, 417.1 [M+H]⁺. ¹HNMR (600 MHz, CD₃OD) δ 8.69 (s, 2H), 8.16 (dd, J=8.0, 1.2, 1H), 7.66 (m,1H), 7.61-7.55 (m, 2H), 7.38 (dd, J=7.8, 1.3, 3H), 3.27 (s, 2H), 1.03(s, 6H).

Example 281

5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-4-cyclopropylpiperazine. MS (ESI): masscalcd. for C₂₃H₂₄FN₅O₂S, 453.16; m/z found, 454.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.75 (d, J=0.6, 2H), 8.13 (dd, J=8.0, 1.2, 1H), 7.79-7.74(m, 1H), 7.69-7.59 (m, 2H), 7.45 (dd, J=7.6, 1.2, 1H), 7.37-7.32 (m,2H), 3.59-3.33 (m, 4H), 3.28-3.00 (m, 4H), 2.82 (m, 1H), 1.00-0.86 (m,4H).

Example 282

2-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanoltrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)ethanol. MS (ESI): masscalcd. for C₂₂H₂₄FN₅O₃S, 457.16; m/z found, 458.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.72 (s, 2H), 8.13 (dd, J=8.0, 1.2, 1H), 7.77 (m, 1H),7.71-7.59 (m, 2H), 7.46 (dd, J=7.6, 1.2, 1H), 7.39-7.33 (m, 2H),3.85-3.80 (m, 2H), 3.68-3.33 (m, 4H), 3.26-3.22 (m, 2H), 3.17-2.81 (m,4H).

Example 283

4′-(2-Aminopyrimidin-5-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-(cyclopropylmethyl)benzenesulfonamide. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.67 (s, 2H), 8.10 (dd, J=8.0, 1.4 Hz, 1H), 7.70-7.65 (m,1H), 7.65-7.53 (m, 2H), 7.39-7.35 (m, 1H), 7.31-7.25 (m, 2H), 1.22 (s,3H), 0.52-0.48 (m, 2H), 0.38-0.33 (m, 2H).

Example 284

4′-(2-Aminopyrimidin-5-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-cyclopropylbenzenesulfonamide. MS (ESI): mass calcd. forC₁₉H₁₇FN₄O₂S, 384.10; m/z found, 385.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.68 (d, J=1.0, 2H), 8.11 (dd, J=8.0, 1.2, 1H), 7.69 (m, 1H), 7.62 (m,1H), 7.56 (m, 1H), 7.40 (dd, J=7.6, 1.2, 1H), 7.35-7.22 (m, 2H), 2.20(m, 1H), 0.55-0.34 (m, 4H).

Example 285

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-phenylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₂H₁₇FN₄O₂S, 420.10; m/z found, 421.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.66 (s, 1H), 8.14 (d, J=7.8, 1H), 7.57 (m, 3H), 7.33 (m, 2H), 7.12 (m,4H), 7.02-6.75 (m, 3H).

Example 286

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₉H₁₉FN₄O₃S, 402.11; m/z found, 403.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.59 (d, J=1.3, 2H), 8.07 (dd, J=7.9, 1.4, 1H), 7.68(td, J=7.5, 1.4, 1H), 7.65-7.58 (m, 2H), 7.39 (dd, J=7.5, 1.4, 1H), 7.35(dd, J=11.8, 1.8, 1H), 7.29 (dd, J=7.9, 1.8, 1H), 7.25 (d, J=7.5, 1H),3.30 (dd, J=10.3, 4.9, 1H), 3.14-3.09 (m, 1H), 3.09-3.01 (m, 1H), 0.96(d, J=6.5, 3H).

Example 287

4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-3′-fluoro-3-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

To a 6 mL microwave vial the following were added5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine(60 mg, 0.19 mmol), N-(tert-butyl)-2-chloro-6-methylbenzenesulfonamide(62 mg, 0.24 mmol), andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1-1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(3 mg, 0.004 mmol). The vial was flushed with nitrogen and charged withN₂ sparged THF (0.3 mL) and N₂ sparged K₃PO₄ (0.8 mL, 0.5 M). Theresulting biphasic mixture was stirred at rt for 1 h and at 45° C. for 1h. The resulting mixture was concentrated to dryness and the resultingresidue was purified by HPLC to provide the title compound. MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.1 [M+H]⁺.

Example 288

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-methylbenzenesulfonamide. MS (ESI): mass calcd. forC₁₇H₁₅FN₄O₂S, 358.09; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.59 (s, 2H), 7.93 (dd, J=7.8, 1.4, 1H), 7.70 (td, J=7.5, 1.4, 1H),7.67-7.58 (m, 2H), 7.42 (dd, J=7.5, 1.5, 1H), 7.34 (dd, J=11.8, 1.8,1H), 7.31-7.26 (m, 4H), 2.41 (d, J=4.8, 3H).

Example 289

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamideMethod 1

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide.

Method 2

A mixture of5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine(30.0 g, 95.2 mmol), K₃PO₄ (70.7 g, 333 mmol),(R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide (28.0 g, 95.2mmol), PdCl₂(dppf).CH₂Cl₂ (0.70 g, 0.95 mmol), acetonitrile (476 mL),and water (190 mL) was sparged with N₂ and stirred at 75° Celsius for 26hours. After filtration, water was added and the reaction mixture wascooled to rt. Solid precipitate was collected by vacuum filtration anddried in a vacuum oven at 70° Celsius (24.0 g, 63%). The solid wasrecrystallized from EtOH and treated successively with activatedcharcoal and silica-supported thiol to remove residual Pd and afford thetitle compound (21.6 g, 57%). MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₃S,402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (d,J=1.4, 2H), 8.12-7.99 (m, 1H), 7.73-7.65 (m, 1H), 7.65-7.53 (m, 2H),7.39 (dd, J=7.5, 1.4, 1H), 7.36-7.31 (m, 1H), 7.28 (dd, J=7.9, 1.8, 1H),7.23 (d, J=7.5, 1H), 6.92 (s, 2H), 4.75-4.67 (m, 1H), 3.33-3.27 (m, 1H),3.16-3.01 (m, 2H), 0.96 (d, J=6.4, 3H). Chiral HPLC: Chiralpak IC4.6×250 mm column, 30% EtOH+0.2% TEA, 70% CO₂, 2 mL/min, retention time22.4 min, ee>99%.

Example 290

5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)piperazine. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.63 (s, 2H), 8.54 (d, J=1.0, 2H), 8.08-8.04 (m, 1H), 7.81 (m, 1H),7.74-7.68 (m, 1H), 7.61 (m, 1H), 7.50 (d, J=7.6, 1H), 7.36 (dd, J=11.6,1.5, 1H), 7.29 (dd, J=7.9, 1.7, 1H), 7.05 (s, 2H), 3.04-2.86 (m, 8H).

Example 291

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (R)-2-bromo-N-(2,2,2-trifluoro-1-phenylethyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₄H₁₈F₄N₄O₂S, 502.11; m/z found, 503.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆) δ 9.28 (d, J=10.1, 1H), 8.54 (d, J=1.2, 2H),7.88 (dd, J=8.1, 1.1, 1H), 7.59 (m, 1H), 7.53 (t, J=8.3, 1H), 7.46-7.40(m, 3H), 7.41-7.30 (m, 3H), 7.27 (dd, J=7.6, 1.2, 1H), 7.12-6.97 (m,4H), 5.14-4.96 (m, 1H).

Example 292

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(2,2,2-trifluoro-1-phenylethyl)benzene-sulfonamide. MS(ESI): mass calcd. for C₂₄H₁₈F₄N₄O₂S, 502.11; m/z found, 503.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆) δ 9.29 (d, J=10.1, 1H), 8.59 (s, 2H), 7.88(dd, J=8.0, 1.0, 1H), 7.60 (m, 1H), 7.54 (t, J=8.2, 1H), 7.47-7.42 (m,3H), 7.38-7.31 (m, 3H), 7.27 (dd, J=7.6, 1.0, 1H), 7.11-7.04 (m, 2H),5.11-5.03 (m, 1H).

Example 293

5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 1-bromo-2-(tert-butylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₀H₂₀FN₃O₂S, 385.12; m/z found, 386.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.57 (d, J=0.8, 2H), 8.03 (dd, J=8.0, 1.2, 1H), 7.81 (m, 1H), 7.72 (m,1H), 7.56 (m, 1H), 7.41 (dd, J=7.6, 1.2, 1H), 7.32 (dd, J=11.9, 1.6,1H), 7.25 (dd, J=7.9, 1.7, 1H), 7.14 (s, 2H), 1.08 (s, 9H).

Example 294

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-isobutylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.53 (s, 2H), 7.94 (dd, J=7.9, 1.0, 1H), 7.68 (m, 1H), 7.65-7.57 (m,2H), 7.52 (m, 1H), 7.41 (dd, J=7.5, 1.1, 1H), 7.33 (dd, J=11.8, 1.4,1H), 7.29 (dd, J=7.9, 1.6, 1H), 7.03 (s, 2H), 2.53 (t, J=6.4, 2H), 1.60(m, 1H), 0.79 (d, J=6.7, 6H).

Example 295

4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-ethylbenzenesulfonamide. MS (ESI): mass calcd. forC₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.57 (d, J=1.3, 2H), 7.96 (dd, J=7.9, 1.4, 1H), 7.69 (td, J=7.5, 1.4,1H), 7.66-7.58 (m, 2H), 7.44-7.40 (m, 2H), 7.34 (dd, J=11.8, 1.8, 1H),7.29 (dd, J=7.9, 1.7, 1H), 7.18 (s, 2H), 2.77 (qd, J=7.2, 5.6, 2H), 0.97(t, J=7.2, 3H).

Example 296

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-bromo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene-sulfonamide.MS (ESI): mass calcd. for C₂₀H₁₈F₄N₄O₂S, 454.11; m/z found, 455.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.65 (s, 2H), 8.12 (dd, J=8.0, 1.1,1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.55 (m, 1H), 7.39 (dd, J=7.5, 1.2,1H), 7.32 (dd, J=6.0, 4.7, 2H), 1.29 (s, 6H).

Example 297

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.71 (s, 2H), 8.10 (d, J=7.9, 1H), 7.68 (m,1H), 7.63-7.53 (m, 2H), 7.40-7.34 (m, 1H), 7.33-7.26 (m, 2H), 3.87 (m,1H), 1.23 (d, J=7.0, 3H).

Example 298

5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(pyrrolidin-1-ylsulfonyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.54 (d, J=1.2, 2H), 7.98 (dd, J=7.9, 1.1, 1H), 7.73 (m, 1H),7.67-7.59 (m, 2H), 7.43 (dd, J=7.5, 1.1, 1H), 7.34 (dd, J=11.8, 1.6,1H), 7.28 (dd, J=7.9, 1.7, 1H), 7.05 (s, 2H), 2.88 (t, J=6.7, 4H),1.76-1.60 (m, 4H).

Example 299

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(N,N-dimethyl-sulfamoyl)phenyl)boronic acid MS (ESI): mass calcd. forC₁₈H₁₇FN₄O₂S, 372.10; m/z found, 373.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.56 (d, J=1.1, 2H), 7.95 (dd, J=7.9, 1.2, 1H), 7.73 (m, 1H), 7.66 (m,1H), 7.61 (m, 1H), 7.43 (dd, J=7.5, 1.2, 1H), 7.32 (dd, J=11.8, 1.6,1H), 7.26 (dd, J=7.9, 1.7, 1H), 2.50 (s, 6H).

Example 300

4′-(2-Aminopyrimidin-5-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(N,N-diethyl-sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.54 (d, J=1.3, 2H), 7.96 (dd, J=208.0, 1.2, 1H), 7.71 (m, 1H), 7.63(m, 2H), 7.41 (dd, J=7.5, 1.2, 1H), 7.30 (m, 1H), 7.26 (m, 1H), 7.04 (s,2H), 2.93 (q, J=7.1, 4H), 0.94 (t, J=7.1, 6H).

Example 301

5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(piperidin-1-ylsulfonyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.54 (d, J=1.2, 2H), 7.99 (dd, J=8.0, 1.2, 1H), 7.73 (m, 1H),7.69-7.57 (m, 2H), 7.44 (dd, J=7.6, 1.2, 1H), 7.33 (m, 1H), 7.27 (dd,J=7.9, 1.7, 1H), 7.05 (s, 2H), 2.84-2.74 (m, 4H), 1.43-1.25 (m, 6H).

Example 302

4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

Trifluoroacetic acid (1 mL) was added to neat4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide(52 mg, 0.13 mmol). After 4 hours, the resulting solution wasconcentrated to dryness and purified by HPLC to provide the titlecompound (33 mg, 59%) as a clear glassy solid. MS (ESI): mass calcd. forC₁₆H₁₃FN₄O₂S, 344.07; m/z found, 345.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.54 (d, J=1.3, 2H), 8.05 (dd, J=7.8, 1.4, 1H), 7.70-7.56 (m, 3H),7.40-7.28 (m, 5H), 7.03 (s, 2H).

Example 303

5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(morpholino-sulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.56 (d, J=1.3, 2H), 8.02 (dd, J=8.0, 1.2, 1H), 7.77 (m, 1H), 7.68 (m,1H), 7.62 (m, 1H), 7.46 (dd, J=7.6, 1.2, 1H), 7.38 (dd, J=11.8, 1.6,1H), 7.31 (dd, J=7.9, 1.7, 1H), 3.46-3.37 (m, 4H), 2.83-2.73 (m, 4H).

Example 304

5-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(methyl-sulfonyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₁₇H₁₄FN₃O₂S, 343.08; m/z found, 344.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.57 (d, J=1.3, 2H), 8.12 (dd, J=208.0, 1.2, 1H), 7.80 (m, 1H), 7.72(m, 1H), 7.65 (m, 1H), 7.46 (dd, J=7.5, 1.2, 1H), 7.40 (dd, J=11.7, 1.7,1H), 7.33 (dd, J=7.9, 1.7, 1H), 2.96 (s, 3H).

Example 305

4′-(2-Aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 287 using5-(4-chloro-2-fluorophenyl)pyrimidin-2-amine and(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.55 (s, 2H), 8.06 (dd, J=7.9, 1.3, 1H), 7.66 (m, 1H),7.63-7.57 (m, 2H), 7.38 (dd, J=7.5, 1.2, 1H), 7.33 (dd, J=11.9, 1.5,1H), 7.28 (dd, J=7.9, 1.6, 1H), 6.99-6.88 (m, 1H), 1.03 (s, 9H).

Example 306

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-onetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd.for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 7.22 (d, J=0.7, 2H), 6.61 (m, 1H), 6.22 (m, 1H), 6.12 (m, 1H),6.07 (dd, J=11.3, 4.9, 1H), 5.92 (dd, J=7.6, 1.2, 1H), 5.82 (t, J=1.8,1H), 5.80 (dd, J=5.4, 1.4, 1H), 1.81 (s, 2H), 1.63 (m, 4H).

Example 307

tert-ButylN-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate

The title compound was prepared using analogous conditions to thosedescribed in Example 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand (S)-tert-butyl 2-(2-bromophenylsulfonamido)propanoate. MS (ESI):mass calcd. for C₂₃H₂₅FN₄O₄S, 472.16; m/z found, 473.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.65 (d, J=1.1, 2H), 8.08 (dd, J=8.0, 1.2, 1H), 7.66(m, 1H), 7.61-7.49 (m, 2H), 7.37 (m, 3H), 3.66 (q, J=107.2, 1H), 1.34(s, 9H), 1.26 (d, J=7.2, 3H).

Example 308

N-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alanine

Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butylN-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate(80 mg, 0.17 mmol) in DCM (1 mL) at rt. After 2 hours, the solution wasconcentrated to dryness and purified by HPLC to afford the titlecompound (70 mg, 89%). MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₄S, 416.10;m/z found, 417.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.72 (s, 2H), 8.10(dd, J=8.0, 1.2, 1H), 7.66 (m, 1H), 7.61-7.53 (m, 2H), 7.37 (m, 3H),3.73 (q, J=7.2, 1H), 1.31 (d, J=7.2, 3H).

Example 309

N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand N-(2-bromophenyl)pyrrolidine-1-sulfonamide MS (ESI): mass calcd. forC₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.63 (s, 2H), 7.59 (d, J=8.4, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.32-7.29(m, 2H), 7.24-7.22 (m, 1H), 7.22-7.15 (m, 1H), 6.87-6.79 (m, 2H), 6.36(s, 1H), 3.37-3.26 (m, 4H), 1.94-1.83 (m, 4H).

Example 310

N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O₃S, 429.13; m/z found, 430.4 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.63 (d, J=1.2, 2H), 7.70-7.54 (m, 2H), 7.48-7.25 (m, 5H), 3.70-3.55 (m,4H), 3.05 (dd, J=5.7, 3.8, 4H).

Example 311

N′-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand N-(2-bromophenyl)-N,N-dimethylsulfonamide. MS (ESI): mass calcd. forC₁₈H₁₈FN₅O₂S, 387.12; m/z found, 388.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.57 (d, J=1.4, 2H), 7.61-7.55 (m, 1H), 7.50 (m, 1H), 7.42-7.35 (m, 1H),7.24-7.21 (m, 1H), 7.21-7.17 (m, 2H), 6.36 (s, 1H), 5.17 (s, 2H), 2.82(s, 6H).

Example 312

5-(2′-(2-Oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrimidin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing6-((2-bromophenyl)sulfonyl)-2-oxa-6-azaspiro[3.3]heptanes and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₃S, 426.12; m/z found, 426.9 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s, 2H), 8.05-7.96 (d, J=7.9, 1H),7.78-7.71 (m, 1H), 7.68-7.58 (m, 2H), 7.47-7.41 (d, J=7.5, 1H),7.35-7.28 (m, 1H), 7.28-7.23 (m, 1H), 6.90 (s, 2H), 4.51 (d, J=1.3, 4H),3.71 (d, J=1.4, 4H).

Example 313

6-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing6-((2-bromophenyl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxideand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₄S₂, 474.08; m/z found, 474.8[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56-8.50 (d, J=1.4, 2H), 8.05-7.99(dd, J=8.0, 1.3, 1H), 7.80-7.73 (m, 1H), 7.69-7.60 (m, 2H), 7.48-7.43(dd, J=7.6, 1.3, 1H), 7.38-7.32 (dd, J=11.8, 1.8, 1H), 7.31-7.26 (dd,J=7.9, 1.7, 1H), 6.90 (s, 2H), 4.32 (s, 4H), 3.76 (s, 4H).

Example 314

1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)azetidine-3-carbonitrile

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing1-((2-bromophenyl)sulfonyl)azetidine-3-carbonitrile and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₆FN₅O₂S, 409.10; m/z found, 409.9 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 2H), 8.08-8.00 (d, J=8.0, 1H),7.83-7.75 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.51-7.43 (d,J=7.5, 1H), 7.38-7.31 (d, J=11.7, 1H), 7.31-7.26 (m, 1H), 6.89 (s, 2H),3.96-3.87 (m, 2H), 3.68-3.59 (m, 3H).

Example 315

1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing1-((2-bromophenyl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O₃S, 468.09; m/z found, 469.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.53-8.47 (d, J=1.4, 2H), 8.06-8.01(dd, J=8.0, 1.3, 1H), 7.81-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.64-7.58(m, 1H), 7.51-7.45 (m, 2H), 7.35-7.29 (dd, J=11.7, 1.8, 1H), 7.28-7.24(dd, J=7.8, 1.7, 1H), 6.94 (s, 2H), 3.81-3.76 (d, J=9.3, 2H), 3.71-3.66(m, 2H)

Example 316

5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 4-((2-bromophenyl)sulfonyl)tetrahydro-2H-thiopyran 1,1-dioxide. MS(ESI): mass calcd. for C₂₁H₂₀FN₃O₄S₂, 461.09; m/z found, 461.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.06 (d, J=7.9, 1H), 7.85 (m,1H), 7.76 (m, 1H), 7.61 (m, 1H), 7.49 (d, J=7.5, 1H), 7.37 (d, J=11.6,1H), 7.30 (d, J=8.0, 1H), 6.94 (s, 2H), 3.26-3.07 (m, 5H), 2.12-2.09 (m,2H), 2.01-1.86 (m, 2H).

Example 317

2-(((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)methyl)quinazolin-4(3H)-one

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 2-(((2-bromophenyl)sulfonyl)methyl)quinazolin-4(3H)-one. MS (ESI):mass calcd. for C₂₅H₁₈FN₅O₃S, 487.11; m/z found, 487.9 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.60-8.43 (d, J=1.4, 2H), 8.12-8.02(dd, J=8.0, 1.5, 1H), 7.96-7.89 (dd, J=8.0, 1.3, 1H), 7.84-7.71 (m, 2H),7.66-7.42 (m, 4H), 7.42-7.22 (m, 3H), 6.91 (s, 2H), 4.37 (s, 2H).

Example 318

1-(3-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amineand 1-(3-((2-bromophenyl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one.MS (ESI): mass calcd. for C₂₆H₂₂FN₅O₃S, 503.14; m/z found, 503.9 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.45 (s, 2H), 8.12-8.03 (d,J=7.8, 1H), 7.83-7.75 (m, 1H), 7.75-7.66 (m, 1H), 7.45-7.30 (m, 2H),7.27-7.19 (d, J=11.5, 1H), 7.09-6.88 (m, 6H), 3.79-3.72 (t, J=6.5, 2H),2.97-2.88 (dd, J=9.7, 6.3, 2H), 1.79-1.68 (m, 2H).

Example 319

5-(2′-{[3-(Cyclohexylsulfonyl)propyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using1-bromo-2-((3-(cyclohexylsulfonyl)propyl)sulfonyl)benzene and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₅H₂₈FN₃O₄S₂, 517.15; m/z found, 518.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.59-8.51 (d, J=1.4, 2H), 8.20-8.14(dd, J=8.0, 1.3, 1H), 7.82-7.76 (m, 1H), 7.72-7.67 (m, 1H), 7.59-7.52(m, 1H), 7.51-7.46 (dd, J=7.7, 1.3, 1H), 7.38-7.31 (m, 2H), 3.16-3.08(t, J=7.5, 2H), 3.08-3.01 (t, J=7.3, 2H), 2.94-2.82 (m, 1H), 2.07-1.97(m, 4H), 1.91-1.80 (m, 2H), 1.79-1.62 (d, J=13.0, 1H), 1.48-1.35 (m,2H), 1.35-1.25 (m, 2H), 1.24-1.12 (m, 1H).

Example 320

5-{3-Fluoro-2′-[(1-methyl-1H-benzimidazol-2-yl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using2-((2-bromophenyl)sulfonyl)-1-methyl-1H-benzo[d]imidazole and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₄H₁₈FN₅O₂S, 459.12; m/z found, 460.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 7.03-6.96 (dd, J=7.8, 1.5, 1H), 6.88-6.86 (d,J=1.4, 2H), 6.43-6.28 (m, 1.5, 2H), 6.15-6.09 (d, J=8.2, 1H), 6.08-5.99(m, 2H), 5.97-5.86 (m, 2H), 5.64-5.53 (m, 1H), 5.34-5.30 (dd, J=7.8,1.7, 1H), 5.30-5.23 (dd, J=11.3, 1.7, 1H), 2.22 (s, 3H).

Example 321

5-(2′-{[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using5-(((2-bromophenyl)sulfonyl)methyl)-3-cyclopropyl-1,2,4-oxadiazole and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₈FN₅O₃S, 451.11; m/z found, 452.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.56 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.77(dd, J=8.2, 6.9, 1H), 7.67-7.61 (m, 1H), 7.61-7.57 (m, 1H), 7.52-7.46(d, J=7.6, 1H), 7.39-7.35 (dd, J=7.9, 1.6, 1H), 7.35-7.31 (m, 1H),2.05-1.94 (m, 1H), 1.04-0.94 (m, 1H), 0.79-0.72 (m, 1H).

Example 322

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-5-(trifluoromethyl)benzenesulfonamide and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₇H₁₂F₄N₄O₂S, 412.06; m/z found, 413.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.43-8.40(m, 1H), 7.98-7.92 (d, J=7.7, 1H), 7.63-7.58 (d, J=8.0, 1H), 7.58-7.52(m, 1H), 7.37-7.35 (m, 1H), 7.35-7.32 (m, 1H).

Example 323

5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 1-bromo-2-(methylsulfonyl)-4-(trifluoromethyl)benzeneand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₃F₄N₃O₂S, 411.07; m/z found, 412.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61-8.51 (d, J=1.4, 2H), 8.44 (s,1H), 8.11-8.05 (d, J=7.5, 1H), 7.72-7.66 (d, J=8.0, 1H), 7.66-7.59 (m,1H), 7.45-7.35 (m, 2H), 2.89 (s, 3H).

Example 324

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one

The title compound was prepared in a manner similar to that described inExample 88 using4-((2-bromo-5-(trifluoromethyl)phenyl)-sulfonyl)-piperazin-2-one and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₇F₄N₅O₃S, 495.10; m/z found, 496.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.70-8.61 (d, J=1.2, 2H), 8.40 (s,1H), 8.10-8.03 (d, J=157.7, 1H), 7.71-7.64 (d, J=7.9, 1H), 7.64-7.58 (m,1H), 7.39-7.37 (m, 1H), 7.36 (s, 1H), 3.34 (s, 2H), 3.22-3.17 (m, 2H),3.17-3.12 (m, 2H).

Example 325

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-methyl-5-(trifluoromethyl)benzenesulfonamideand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₄F₄N₄O₂S, 426.08; m/z found, 427.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.57-8.52 (d, J=1.4, 2H), 8.33-8.27(m, 1H), 8.02-7.94 (m, 1H), 7.66-7.60 (d, J=7.9, 1H), 7.60-7.52 (m, 1H),7.38-7.31 (m, 2H), 2.46 (s, 3H).

Example 326

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzene-sulfonamide and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₆F₄N₄O₃S, 456.09; m/z found, 457.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.57-8.53 (d, J=1.4, 2H), 8.38-8.35(m, 1H), 8.00-7.96 (dd, J=8.1, 1.5, 1H), 7.63-7.60 (d, J=8.0, 1H),7.59-7.54 (m, 1H), 7.38-7.36 (dd, J=6.1, 1.6, 1H), 7.36-7.34 (m, 1H),3.51-3.45 (t, J=5.9, 2H), 2.95-2.86 (t, J=5.9, 2H).

Example 327

4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamideand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₆F₄N₄O₂S, 440.09; m/z found, 441.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.56-8.53 (d, J=1.4, 2H), 8.34-8.31(m, 1H), 7.99-7.95 (m, 1H), 7.63-7.59 (d, J=8.0, 1H), 7.59-7.53 (m, 1H),7.36-7.34 (dd, J=7.1, 1.6, 1H), 7.34-7.32 (m, 1H), 2.97-2.71 (q, J=7.2,2H), 1.15-0.84 (t, J=7.2, 3H).

Example 328

5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using1-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₂₁F₄N₅O₂S, 495.14; m/z found, 496.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.63-8.61 (d, J=1.4, 2H), 8.40-8.37(d, J=1.4, 1H), 8.10-8.05 (m, 1H), 7.70-7.67 (d, J=8.0, 1H), 7.67-7.63(m, 1H), 7.46-7.30 (m, 2H), 2.86 (s, 3H), 3.83-2.53 (br m, 8H).

Example 329

5-{2′-[(5-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and5-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 391.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d,J=1.4, 2H), 7.95 (s, 2H), 7.66-7.59 (m, 1H), 7.55-7.48 (m, 2H),7.46-7.41 (m, 2H), 7.27-7.20 (m, 2H), 6.89 (s, 2H), 5.45 (s, 2H).

Example 330

5-{2′-[(4-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 2134′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and4-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 390.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d,J=1.4, 2H), 7.80 (d, J=5.8, 1H), 7.73-7.66 (m, 1H), 7.57-7.50 (m, 2H),7.48-7.44 (m, 2H), 7.32-7.23 (m, 2H), 6.90-6.88 (m, 4H), 6.11 (d, J=5.8,1H).

Example 331

5-{2′-[(5-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and5-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d,J=1.4, 2H), 8.16 (s, 1H), 7.92 (s, 1H), 7.59-7.49 (m, 3H), 7.49-7.44 (m,2H), 7.30-7.20 (m, 2H), 6.89 (s, 2H), 5.44 (s, 2H).

Example 332

5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₄FN₅S, 375.10; m/zfound, 375.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 2H), 8.56 (d,J=4.9, 2H), 7.79-7.73 (m, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H),7.33-7.24 (m, 2H), 7.21 (m, 1H), 6.23 (s, 2H).

Example 333

5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and2-chloropyrazine. MS (ESI): mass calcd. for C₂₀H₁₄FN₅S, 375.10; m/zfound, 375.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70-8.57 (m, 2H), 8.41(dd, J=2.5, 1.6, 1H), 8.35 (d, J=2.6, 1H), 8.27 (d, J=1.5, 1H), 7.72(dd, J=8.0, 1.2, 1H), 7.64-7.57 (m, 2H), 7.56-7.50 (m, 2H), 7.34 (d,J=11.8, 1H), 7.27 (d, J=8.0, 1H), 6.01 (s, 2H).

Example 334

5-{2′-[(6-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and4-amino-6-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 390.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d,J=1.4, 2H), 8.06 (s, 1H), 7.77-7.71 (m, 1H), 7.68-7.61 (m, 1H),7.60-7.52 (m, 3H), 7.29 (dd, J=11.9, 1.5, 1H), 7.25 (dd, J=7.9, 1.7,1H), 6.88 (s, 2H), 6.78 (s, 2H), 5.78 (d, J=0.9, 1H).

Example 335

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 213 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and2-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S,390.11; m/z found, 390.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d,J=1.3, 2H), 7.90 (d, J=5.3, 1H), 7.78-7.71 (m, 1H), 7.68-7.61 (m, 1H),7.59-7.51 (m, 3H), 7.30 (dd, J=11.8, 1.6, 1H), 7.25 (dd, J=7.9, 1.7,1H), 6.89 (s, 2H), 6.64 (s, 2H), 5.86 (d, J=5.3, 1H).

Example 336

5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and2-amino-6-chloropyrazine. MS (ESI): mass calcd. for C₂₀H₁₅FN₆S, 390.11;m/z found, 391.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.3,2H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 3H), 7.49-7.46 (m, 2H), 7.31 (dd,J=11.9, 1.5, 1H), 7.26 (dd, J=7.9, 1.7, 1H), 7.18 (s, 1H), 6.90 (s, 2H),6.57 (s, 2H).

Example 337

5-{2′-[(5-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride

To a solution of5-{2′-[(5-aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}-pyrimidin-2-amine(200 mg, 0.51 mmol) in MeCN/DCM/H₂O (5 mL/5 mL/5 mL) were added NaIO₄(326 mg, 1.50 mmol) and RuCl₃ (16 mg, 0.075 mmol). The reaction mixturewas stirred at rt for 10 hours then poured into water (50 mL) andextracted with EtOAc (30 mL×3). The combined organic extracts wereconcentrated and purified by HPLC to give the title compound as a whitesolid. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/z found, 423.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 2H), 8.30-8.25 (m, 2H),8.22 (s, 1H), 7.83 (m, 1H), 7.77 (m, 1H), 7.44-7.33 (m, 2H), 6.88 (d,J=9.5, 2H), 6.29 (s, 2H).

Example 338

5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrimidin-2-amineformate salt

The title compound was prepared using analogous conditions to thosedescribed in Example 337 utilizing5-[3-fluoro-2′-({[2-(trimethylsilyl)-ethoxy]methyl}-sulfanyl)-biphenyl-4-yl]pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₂₆FN₃O₃SSi, 459.14; m/z found, 460.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 2H), 8.19 (dd, J=7.9, 1.4,1H), 7.79 (m, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.46 (dd, J=7.5, 1.3,1H), 7.34-7.31 (m, 2H), 4.36 (s, 2H), 3.80-3.68 (m, 2H), 0.87-0.76 (m,2H), 0.08 (s, 9H).

Example 339

5-{2′-[(5-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride

The title compound was prepared using analogous conditions to thosedescribed in Example 337 utilizing5-{2′-[(5-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/z found,423.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.34 (dd, J=7.7,1.5, 1H), 7.94 (s, 2H), 7.79-7.69 (m, 2H), 7.44 (m, 1H), 7.34 (dd,J=7.3, 1.4, 1H), 6.93 (dd, J=7.9, 1.6, 1H), 6.88 (dd, J=11.5, 1.5, 1H).

Example 340

5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (2-(((2-bromophenyl)thio)methoxy)ethyl)trimethylsilane. MS (ESI):mass calcd. for C₂₂H₂₆FN₃OSSi, 427.16; m/z found, 428.0 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.47 (d, J=1.4, 2H), 7.69 (dd, J=7.7, 1.1, 1H), 7.44(m, 1H), 7.34-7.15 (m, 5H), 4.86 (s, 2H), 3.60-3.47 (m, 2H), 0.88-0.76(m, 2H), 0.06 (s, 9H)

Example 341

5-(3-Fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amineStep A: 5-(4-Chloro-2-fluorophenyl)pyridin-2-amine

Solid 4-chloro-2-fluorobenzeneboronic acid (10.0 g, 57.4 mmol),2-amino-5-bromopyridine (9.92 g, 57.4 mmol), palladium (II)trifluoroacetate (0.381 g, 1.15 mmol), and triphenylphosphine (0.602 g,2.29 mmol) were combined in a 1 L flask under nitrogen, then toluene(150 mL), EtOH (150 mL), and 2 M Na₂CO₃ (100 mL) were added. The mixturewas sparged with nitrogen for 30 min using a gas dispersion tube, thenheated at 80° Celsius for 20 hours with vigorous stirring. The mixturewas cooled to rt, diluted with EtOAc (200 mL), and transferred to aseparatory funnel. The aqueous phase was removed, and the organic phasewashed with brine. The combined aqueous phases were extracted with anequal volume of EtOAc, and the combined organic phases were dried andconcentrated to dryness. The residue was subjected to FCC to provide5-(4-chloro-2-fluorophenyl)pyridin-2-amine (9.10 g, 71%). MS (CI): masscalcd. for C₁₁H₈CFN₂, 222.04; m/z found, 223.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.54-8.22 (s, 2H), 8.22-8.18 (d, J=2.1, 1H), 8.15-8.10 (m,1H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 1H), 7.16-7.06 (d, J=9.3, 1H).

Step B:5-(3-Fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (100 mg, 0.449 mmol),2-(methylsulfonyl)phenylboronic acid (112 mg, 0.561 mmol), andchloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)(33 mg, 0.045 mmol) were placed in a sealable reaction tube undernitrogen. THF (2 mL, sparged with nitrogen) and K₃PO₄ (2 mL, 0.5 Msparged with nitrogen) were added, and the reaction vessel was sealedand heated at 60° Celsius for 16 hours with vigorous stirring. Themixture was cooled to rt, diluted with EtOAc, and washed with 2 M K₂CO₃,then dried and concentrated to dryness. The residue was subjected to FCCto provide the title compound (45 mg, 29%). MS (CI): mass calcd. forC₁₈H₁₅FN₂O₂S, 342.08; m/z found, 343.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.38-8.31 (s, 1H), 8.29-8.22 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.65 (m,1H), 7.64-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.36-7.27(m, 2H), 6.64-6.59 (m, 1H), 4.66-4.51 (s, 2H), 2.81-2.69 (s, 2H).

Example 342

4′-(6-Aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 341, using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid inStep B. MS (CI): mass calcd. for C₂₁H₂₂FN₃O₂S, 399.14; m/z found, 400.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.22-8.13 (s, 1H), 8.10-8.03 (d,J=7.8, 1H), 7.67-7.57 (m, 3H), 7.53-7.48 (m, 1H), 7.40-7.36 (d, J=7.4,1H), 7.31-7.22 (m, 2H), 6.94-6.89 (s, 1H), 6.60-6.52 (d, J=8.6, 1H),6.24-6.11 (s, 2H), 1.07-0.99 (s, 9H).

Example 343

4′-(6-Aminopyridin-3-yl)-N,N-diethyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 341, using (2-(N,N-diethylsulfamoyl)phenyl)boronic acid in StepB. MS (CI): mass calcd. for C₂₁H₂₂FN₃O₂S, 399.14; m/z found, 400.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.28-8.22 (d, J=1.9, 1H), 8.18-8.12(d, J=9.3, 1H), 8.12-7.88 (m, 1H), 7.76-7.69 (m, 1H), 7.68-7.59 (m, 2H),7.43-7.38 (dd, J=7.5, 1.1, 1H), 7.37-7.32 (m, 1H), 7.32-7.27 (m, 1H),7.09-7.04 (d, J=9.2, 1H), 2.99-2.90 (m, 3H), 1.00-0.90 (m, 4H).

The title compound was prepared in a manner similar to that described in

Example 344

5-(3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

The title compound was prepared in a manner similar to that described inExample 341, using (2-(pyrrolidin-1-ylsulfonyl)phenyl)boronic acid inStep B. MS (CI): mass calcd. for C₂₁H₂₀FN₃O₂S, 397.13; m/z found, 398.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.37-8.11 (m, 4H), 8.01-7.95 (m,1H), 7.77-7.71 (m, 1H), 7.69-7.61 (m, 2H), 7.44-7.36 (m, 2H), 7.35-7.30(m, 1H), 7.15-7.10 (d, J=9.3, 1H), 2.99-2.80 (m, 4H), 1.77-1.62 (m, 4H).

Example 345

5-(3-Fluoro-2′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

The title compound was prepared in a manner similar to that described inExample 341, using (2-(piperidin-1-ylsulfonyl)phenyl)boronic acid inStep B. MS (CI): mass calcd. for C₂₂H₂₂FN₃O₂S, 411.14; m/z found, 412.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.47-8.16 (m, 4H), 8.02-7.96 (m,1H), 7.79-7.72 (m, 1H), 7.71-7.60 (m, 2H), 7.46-7.36 (m, 2H), 7.35-7.29(m, 1H), 7.16-7.11 (d, J=9.3, 1H), 2.86-2.74 (m, 4H), 1.45-1.27 (m, 6H).

Example 346

4′-(6-Aminopyridin-3-yl)-N-cyclohexyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamideStep A: (4-(6-Aminopyridin-3-yl)-3-fluorophenyl)boronic acid

5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (2.0 g, 9.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.9 g, 11.0mmol),chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.14 g, 0.18 mmol), and KOAc (2.7 g, 27 mmol) were combined in asealable reaction vessel under nitrogen, and then treated with anhydrous1,4-dioxane (100 mL, sparged with nitrogen). The vessel was sealed andthen heated at 80° Celsius for 16 hours. The mixture was cooled to rt,HCl (1 m, 50 mL) was added and the mixture stirred for 20 min. Themixture was then diluted with EtOAc (200 mL) and the aqueous phase wascollected. The organic phase was extracted with 1 M HCl (2×75 mL). Thecombined aqueous phases were cooled in an icebath and the pH wasadjusted to ca. 7 using solid sodium bicarbonate. The resultingprecipitate was collected by filtration, washed well with water, anddried to provide the title compound (2.1 g, 98%). MS (CI): mass calcd.for C₁₁H₁₀BFN₂O₂, 232.08; m/z found, 233.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.29-8.20 (s, 2H), 8.18-8.13 (s, 1H), 7.80-7.72 (m, 1H),7.69-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.51-7.44 (m, 1H), 6.84-6.57 (m,3H).

Step B:4′-(6-Aminopyridin-3-yl)-N-cyclohexyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

A mixture of (4-(6-aminopyridin-3-yl)-3-fluorophenyl)boronic acid (75mg, 0.32 mmol), 2-bromo-N-cyclohexylbenzenesulfonamide (0.11 g, 0.36mmol), 1,1′-bis[di-tert-butylphosphino)ferrocene]palladium(II) chloride(11 mg, 0.016 mmol), K₂CO₃ (2 M, 1.6 mL, sparged with nitrogen) and THF(2 mL, sparged with nitrogen) were combined in a sealed vessel undernitrogen. The mixture was vigorously stirred at rt for 16 hours, thendiluted with EtOAc. The aqueous phase was removed and the organic layerwas dried and concentrated. The residue was subjected to FCC to providethe title compound (15 mg, 11%). MS (CI): mass calcd. for C₂₃H₂₄FN₃O₂S,425.16; m/z found, 426.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.20-8.14(s, 1H), 8.05-7.96 (m, 1H), 7.70-7.57 (m, 3H), 7.55-7.47 (m, 1H),7.44-7.35 (m, 2H), 7.30-7.20 (m, 2H), 6.59-6.52 (d, J=8.6, 1H),6.23-6.11 (s, 2H), 2.83-2.69 (d, J=7.4, 1H), 1.68-1.52 (m, 4H),1.49-1.38 (s, 1H), 1.19-0.92 (m, 6H).

Example 347

(S)-4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

A mixture of (4-(6-aminopyridin-3-yl)-3-fluorophenyl)boronic acid (100mg, 0.43 mmol), (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide(160 mg, 0.54 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (18 mg, 0.022 mmol), K₂CO₃ (340mg, 2.4 mmol), and DMSO (3 mL) was sparged with nitrogen, then thereaction vessel was sealed and heated at 80° Celsius for 16 hours. Themixture was cooled to rt, then filtered, and subjected to HPLCpurification to provide the title compound. MS (CI): mass calcd. forC₂₀H₂₀FN₃O₃S, 401.12; m/z found, 402.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.31-7.93 (m, 5H), 7.72-7.57 (m, 3H), 7.42-7.25 (m, 4H), 7.11-7.04 (d,J=9.2, 1H), 3.34-3.25 (s, 1H), 3.18-3.00 (m, 2H), 1.00-0.91 (d, J=6.5,3H).

Example 348

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-iso-butyl-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using 2-bromo-N-iso-butylbenzenesulfonamide. MS (CI): masscalcd. for C₂₁H₂₂FN₃O₂S, 399.14; m/z found, 400.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.26-8.19 (d, J=2.1, 1H), 8.18-8.11 (d, J=9.2, 1H),8.08-7.79 (m, 3H), 7.72-7.53 (m, 4H), 7.43-7.30 (m, 3H), 7.08-7.00 (d,J=9.2, 1H), 2.57-2.52 (m, 2H), 1.66-1.56 (m, 1H), 0.82-0.75 (d, J=6.7,6H).

Example 349

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(tert-pentyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using 2-bromo-N-(tert-pentyl)benzenesulfonamide. MS (CI):mass calcd. for C₂₂H₂₄FN₃O₂S, 413.16; m/z found, 414.2 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.23-8.19 (d, J=2.0, 1H), 8.19-8.11 (d, J=9.0, 1H),8.10-8.05 (m, 1H), 8.05-7.79 (s, 2H), 7.69-7.57 (m, 3H), 7.40-7.29 (m,3H), 7.09-7.02 (d, J=9.2, 1H), 6.98-6.91 (s, 1H), 1.48-1.36 (m, 2H),1.04-0.91 (s, 6H), 0.79-0.67 (m, 3H).

Example 350

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using2-bromo-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzenesulfonamide. MS(CI): mass calcd. for C₂₁H₁₉F₄N₃O₂S, 453.11; m/z found, 454.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.28-8.19 (m, 2H), 8.17-8.11 (d, J=9.1, 1H),8.07-8.02 (m, 1H), 8.03-7.80 (s, 2H), 7.74-7.65 (m, 2H), 7.64-7.58 (m,1H), 7.43-7.39 (m, 1H), 7.38-7.32 (m, 1H), 7.32-7.28 (dd, J=7.9, 1.7,1H), 7.07-7.00 (d, J=9.2, 1H), 1.29-1.17 (s, 6H).

Example 351

(S)-4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using(S)-2-bromo-N-(2,2,2-trifluoro-1-phenylethyl)benzenesulfonamide. MS(CI): mass calcd. for C₂₅H₁₉F₄N₃O₂S, 501.11; m/z found, 502.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.32-9.24 (d, J=10.1, 1H), 8.24-8.20 (d, J=2.1,1H), 8.20-8.11 (d, J=9.2, 1H), 8.11-7.90 (s, 2H), 7.90-7.85 (m, 1H),7.64-7.58 (m, 1H), 7.57-7.51 (m, 1H), 7.49-7.40 (m, 3H), 7.40-7.31 (m,3H), 7.29-7.24 (dd, J=7.6, 1.2, 1H), 7.15-7.03 (m, 3H), 5.22-4.90 (m,1H).

Example 352

(R)-4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using(R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (CI): masscalcd. for C₂₀H₂₀FN₃O₃S, 401.12; m/z found, 402.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.26-8.20 (d, J=2.1, 1H), 8.19-8.11 (d, J=9.2, 1H),8.09-8.05 (m, 1H), 8.05-7.84 (s, 2H), 7.72-7.58 (m, 3H), 7.41-7.35 (m,2H), 7.35-7.27 (m, 2H), 7.08-7.02 (d, J=9.2, 1H), 5.05-4.29 (m, 1H),3.34-3.27 (dd, J=10.3, 5.0, 1H), 3.14-3.02 (m, 2H), 1.00-0.93 (d, J=6.5,3H).

Example 353

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-methylcyclobutyl)-[,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using 2-bromo-N-(1-methylcyclobutyl)benzenesulfonamide. MS(CI): mass calcd. for C₂₂H₂₂FN₃O₂S, 411.14; m/z found, 412.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.24-8.20 (s, 1H), 8.20-8.15 (d, J=9.5, 1H),8.15-7.90 (m, 3H), 7.70-7.58 (m, 3H), 7.55-7.51 (s, 1H), 7.41-7.28 (m,3H), 7.10-7.05 (d, J=9.2, 1H), 2.15-2.05 (m, 2H), 1.71-1.51 (m, 4H),1.26-1.18 (s, 3H).

Example 354

4-((4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine1,1-dioxide

The title compound was prepared in a manner similar to that described inExample 347 using 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide.MS (CI): mass calcd. for C₂₁H₂₀FN₃O₄S₂, 461.09; m/z found, 462.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.27-8.21 (d, J=2.0, 1H), 8.20-8.14 (d,J=9.1, 1H), 8.13-7.88 (m, 3H), 7.82-7.76 (m, 1H), 7.72-7.62 (m, 2H),7.48-7.39 (m, 2H), 7.37-7.31 (m, 1H), 7.10-7.02 (d, J=9.2, 1H),3.12-3.04 (m, 4H), 3.34-3.26 (m, 4H).

Example 355

(S)-4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoropropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using(S)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS (CI):mass calcd. for C₂₀H₁₇F₄N₃O₂S, 439.10; m/z found, 440.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.56-8.49 (d, J=8.9, 1H), 8.26-8.20 (s, 1H),8.20-8.12 (d, J=9.5, 1H), 8.09-7.82 (m, 3H), 7.74-7.59 (m, 3H),7.42-7.37 (m, 1H), 7.36-7.27 (m, 2H), 7.09-7.01 (d, J=9.1, 1H),3.98-3.86 (m, 1H), 1.22-1.11 (d, J=7.0, 3H).

Example 356

5-(2′-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine

The title compound was prepared in a manner similar to that described inExample 347 using(1S,4S)-5-((2-bromophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.1]heptane. MS(CI): mass calcd. for C₂₂H₂₀FN₃O₃S, 425.12; m/z found, 426.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.27-8.23 (d, J=2.0, 1H), 8.20-8.15 (d, J=9.2,1H), 8.15-7.89 (m, 3H), 7.79-7.74 (m, 1H), 7.70-7.62 (m, 2H), 7.47-7.38(m, 2H), 7.37-7.32 (m, 1H), 7.10-7.03 (d, J=9.2, 1H), 4.53-4.47 (s, 1H),4.01-3.96 (s, 1H), 3.63-3.30 (m, 2H), 2.99-2.87 (m, 2H), 1.72-1.61 (d,J=10.0, 1H), 1.47-1.36 (m, 1H).

Example 357

tert-Butyl3-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate

The title compound was prepared in a manner similar to that described inExample 347 using tert-butyl3-((2-bromophenylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate.MS (CI): mass calcd. for C₂₆H₂₉FN₄O₅S, 528.18; m/z found, 529.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.26-8.21 (d, J=2.0, 1H), 8.20-8.13 (d,J=9.4, 1H), 8.11-7.86 (m, 3H), 7.86-7.80 (m, 1H), 7.74-7.67 (m, 1H),7.67-7.58 (m, 2H), 7.44-7.31 (m, 3H), 7.09-7.02 (d, J=9.1, 1H),3.79-3.73 (m, 2H), 3.55-3.52 (m, 2H), 2.93-2.86 (d, J=6.5, 2H),1.40-1.28 (s, 9H).

Example 358

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide

A mixture of tert-butyl3-((2-bromophenylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate(15 mg, 0.028 mmol), TFA (1 mL), and MeOH (1 mL) was maintained at rtfor 2 hours, then concentrated to dryness. The residue was purified byHPLC to provide the title compound (8.0 mg, 52%) MS (CI): mass calcd.for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.84-8.70 (s, 1H), 8.68-8.52 (s, 1H), 8.26-8.19 (d, J=2.1,1H), 8.13-8.03 (d, J=7.4, 1H), 8.01-7.94 (m, 1H), 7.94-7.88 (m, 1H),7.74-7.71 (m, 1H), 7.69-7.65 (m, 1H), 7.63-7.59 (m, 1H), 7.48-7.42 (m,1H), 7.42-7.31 (m, 2H), 7.05-6.91 (d, J=8.8, 1H), 6.33-6.17 (s, 1H),3.94-3.87 (m, 2H), 3.76-3.69 (m, 2H), 3.05-3.00 (d, J=6.5, 2H).

Example 359

2-(1-((4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)ethanol

The title compound was prepared in a manner similar to that described inExample 347 using 2-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)ethanol.MS (CI): mass calcd. for C₂₄H₂₆FN₃O₃S, 455.17; m/z found, 456.3 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.24-8.20 (d, J=2.2, 1H), 8.17-8.09 (d,J=9.1, 1H), 8.02-7.98 (m, 1H), 3.37-3.36 (m, 5H), 7.97-7.78 (s, 2H),7.77-7.73 (m, 1H), 7.69-7.64 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.41 (m,1H), 7.41-7.35 (m, 1H), 7.34-7.30 (dd, J=7.9, 1.7, 1H), 7.07-6.99 (d,J=9.2, 1H), 3.40-3.34 (m, 3H), 3.25-3.21 (d, J=12.3, 2H), 2.43-2.34 (m,2H), 1.59-1.50 (d, J=10.7, 2H), 1.45-1.31 (s, 1H), 1.31-1.20 (m, 2H),0.89-0.78 (m, 2H).

Example 360

1-((4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-ol

The title compound was prepared in a manner similar to that described inExample 347 using 1-((2-bromophenyl)sulfonyl)piperidin-4-ol. MS (CI):mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.2 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.26-8.22 (d, J=2.0, 1H), 8.19-8.15 (d, J=9.4, 1H),8.14-7.92 (m, 3H), 7.78-7.73 (m, 1H), 7.69-7.65 (m, 1H), 7.65-7.60 (m,1H), 7.45-7.40 (dd, J=7.6, 1.2, 1H), 7.40-7.35 (m, 1H), 7.33-7.28 (m,1H), 7.09-7.04 (d, J=9.2, 1H), 3.54-3.52 (m, 2H), 3.09-3.01 (m, 2H),2.69-2.61 (m, 2H), 1.64-1.53 (m, 2H), 1.28-1.17 (m, 2H).

Example 361

(1-((4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)methanol

The title compound was prepared in a manner similar to that described inExample 347 using (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)methanol.MS (CI): mass calcd. for C₂₃H₂₄FN₃O₃S, 441.15; m/z found, 442.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.26-7.94 (m, 5H), 7.78-7.72 (m, 1H),7.70-7.60 (m, 2H), 7.45-7.36 (m, 2H), 7.34-7.30 (dd, J=8.0, 1.6, 1H),7.10-7.04 (d, J=9.2, 1H), 3.29-3.24 (d, J=12.4, 2H), 3.19-3.14 (d,J=6.3, 2H), 2.45-2.36 (m, 2H), 1.60-1.52 (d, J=10.7, 2H), 1.41-1.29 (s,1H), 0.94-0.78 (m, 2H).

Example 362

3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₂H₂₀FN₃O₃S, 425.12; m/z found, 426.0 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 9.57 (s, 1H), 8.29-8.22 (m, 2H), 7.95-7.85 (m, 1H),7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.33 (m, 4H), 7.29 (d, J=7.8,1H), 6.54-6.49 (m, 1H), 5.92 (d, J=6.7, 1H), 3.64-3.51 (m, 1H),3.47-3.34 (m, 2H), 2.34 (s, 1H), 1.03 (d, J=6.5, 3H).

Example 363

3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₀FN₃O₃S, 425.12; m/z found, 426.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.65 (s, 1H), 8.30-8.19 (m, 2H), 7.93-7.84 (m, 1H),7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.44-7.31 (m, 4H), 7.27 (d, J=7.8,1H), 6.56-7.47 (m, 1H), 6.07 (d, J=6.5, 1H), 3.57 (t, J=7.0, 1H),3.49-3.32 (m, 2H), 2.41 (s, 1H), 1.04 (d, J=6.4, 3H).

Example 364

3′-Fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₂₃H₁₉FN₄O₃S, 450.12; m/z found, 451.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ Complex due to the presence of multiple conformationson the NMR time-scale, peaks listed for identification purposes only: δ9.35 (s), 9.23 (s), 8.51-8.42 (m), 8.41-8.31 (m), 8.24-8.17 (m),8.13-8.00 (m), 7.68-7.61 (m), 7.59-7.49 (m), 7.46-7.38 (m), 7.38-7.29(m), 6.57-6.51 (m), 6.38 (s), 6.13 (s), 6.05 (s), 5.68 (s), 3.69-3.57(m), 3.40-3.18 (m), 2.61-2.48 (m), 2.25-1.96 (m).

Example 365

5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₂H₁₇FN₂O₂S, 392.10; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.26 (s, 1H), 8.62-8.52 (m, 1H), 8.24-8.12 (m, 2H), 7.71-7.63 (m, 1H),7.62-7.53 (m, 2H), 7.45-7.31 (m, 4H), 6.64-6.55 (m, 1H), 2.19-2.08 (m,1H), 1.18-1.08 (m, 2H), 0.93-0.82 (m, 2H).

Example 366

3′-Fluoro-N-(2-hydroxyethyl)-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine and3′-fluoro-N-(2-hydroxyethyl)-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide.MS (ESI): mass calcd. for C₂₁H₁₈FN₃O₃S, 411.11; m/z found, 412.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.44-8.41 (m, 1H), 8.24-8.21 (m, 1H),8.14-8.05 (dd, J=8.0, 1.3, 1H), 7.71-7.64 (m, 1H), 7.63-7.55 (m, 2H),7.46-7.44 (d, J=3.5, 1H), 7.44-7.41 (dd, J=7.6, 1.2, 1H), 7.36-7.34 (dd,J=3.8, 1.7, 1H), 7.34-7.31 (dd, J=7.3, 1.4, 1H), 6.59-6.55 (d, J=3.5,1H), 3.52-3.47 (t, J=5.9, 2H), 2.92-2.87 (t, J=5.9, 2H).

Example 367

N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-1H-pyrrolo[2,3-b]pyridine. MS (ESI): masscalcd. for C₂₃H₂₂FN₃O₂S, 423.14; m/z found, 424.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.56-8.45 (m, 2H), 8.18-8.11 (dd, J=8.0, 1.3, 1H),7.70-7.61 (m, 2H), 7.61-7.55 (m, 3H), 7.44-7.35 (m, 3H), 6.76-6.69 (d,J=3.5, 1H), 1.09 (s, 9H).

Example 368

3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared by formingN-tert-butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamidethen removing the tert-butyl group by dissolving the crudeN-tert-butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamidein 1 mL of trifluoroacetic acid and heating it at 60° Celsius for 2hours, after which time the reaction was cooled, concentrated to drynessand purified using FCC. MS (ESI): mass calcd. for C₁₉H₁₄FN₃O₂S, 367.08;m/z found, 368.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.43 (s, 1H),8.26-8.22 (m, 1H), 8.17-8.12 (dd, J=8.0, 1.3, 1H), 7.69-7.62 (m, 1H),7.62-7.55 (m, 2H), 7.47-7.44 (d, J=3.5, 1H), 7.44-7.40 (dd, J=7.6, 1.4,1H), 7.38-7.30 (m, 2H), 6.60-6.56 (d, J=3.5, 1H).

Example 369

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]methanesulfonamideStep A: 2-(4-Bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine

To a 150 mL screw-cap vessel under nitrogen was added5-bromo-4,7-diazaindole (1.0 g, 5.05 mmol), 4-bromo-2-fluorophenylboronic acid (1.33 g, 6.06 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.2 g, 0.24 mmol),K₂CO₃ (2.09 g, 15.2 mmol), 1,4-dioxane (35 mL) and water (13 mL). Themixture was sparged with nitrogen for 10 minutes, the vessel capped andthe reaction heated at 95° Celsius for 24 hours. The reaction was thencooled to rt, diluted with ethyl acetate (200 mL) and washed with water(1×100 mL) and brine (1×100 mL). The organic layer was dried with Na₂SO₄and evaporated to dryness. The crude product was purified by HPLC givingthe title compound (515 mg, 35%). MS (ESI): mass calcd. for C₁₂H₇BrFN₂,290.98; m/z found, 292.0 [M+H]⁺.

Step B

To a mixture of 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (50mg, 0.17 mmol),N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methane-sulfonamide(61 mg, 0.21 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (6.7 mg, 0.009 mmol) in amicrowave vial were added acetonitrile (2.0 mL) and sat. NaHCO₃ (2.0mL). The vial was sparged with nitrogen for 5 min then heated at 110°Celsius for 90 min via microwave irradiation. After cooling to rt, thereaction mixture was diluted with ethyl acetate (50 mL), washed withwater (25 mL) and brine (25 mL), dried (Na₂SO₄) and concentrated todryness. The crude product was purified by HPLC giving the titlecompound (45 mg, 69%). MS (ESI): mass calcd. for C₁₉H₁₅FN₄O₂S, 382.09;m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1H), 8.78(d, J=2.7, 1H), 8.20-8.12 (m, 1H), 7.71-7.64 (m, 2H), 7.48-7.39 (m, 1H),7.37-7.31 (m, 2H), 7.28-7.21 (m, 2H), 6.91 (s, 1H), 6.81-6.75 (m, 1H),2.93 (s, 3H).

Example 370

3′-Fluoro-N,N-dimethyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 usingN,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamidein Step B. MS (ESI): mass calcd. for C₂₀H₁₇FN₄O₂S, 396.11; m/z found,397.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.57 (s, 1H), 8.79 (d, J=2.6,1H), 8.15-8.04 (m, 2H), 7.69-7.59 (m, 2H), 7.58-7.51 (m, 1H), 7.41-7.31(m, 3H), 6.81-6.74 (m, 1H), 2.48 (s, 6H).

Example 371

N-tert-Butyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid in Step B. MS (ESI):mass calcd. for C₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.69 (d, J=2.6, 1H), 8.13-8.04 (m, 1H), 8.03-7.93(m, 2H), 7.74-7.55 (m, 2H), 7.47-7.32 (m, 3H), 7.02 (s, 1H), 6.73 (d,J=3.6, 1H), 1.04 (s, 9H).

Example 372

2-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-(pyrrolidin-1-ylsulfonyl)phenyl)boronic acid in Step B. MS (ESI):mass calcd. for C₂₂H₁₉FN₄O₂S, 422.12; m/z found, 423.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.22 (br s, 1H), 8.83 (d, J=2.5, 1H), 8.24 (d, J=2.5,1H), 8.19-8.13 (m, 1H), 8.14-8.07 (m, 1H), 7.96-7.90 (m, 1H), 7.72-7.65(m, 1H), 7.65-7.58 (m, 1H), 7.57-7.49 (m, 1H), 7.49-7.30 (m, 1H),6.88-6.79 (m, 1H), 3.02-2.90 (m, 3H), 1.77-1.66 (m, 3H), 1.59 (s, 2H).

Example 373

N,N-Diethyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(N,N-diethylsulfamoyl)phenyl)boronicacid in Step B. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂S, 424.14; m/zfound, 425.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.83 (d,J=2.5, 1H), 8.15-8.05 (m, 2H), 7.71-7.66 (m, 1H), 7.63-7.56 (m, 1H),7.55-7.48 (m, 1H), 7.39-7.30 (m, 3H), 6.86-6.82 (m, 1H), 3.03-2.88 (m,4H), 1.00 (t, J=7.15, 6H).

Example 374

2-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(piperidin-1-ylsulfonyl)phenyl)boronicacid in Step B. MS (ESI): mass calcd. for C₂₃H₂₁FN₄O₂S, 436.14; m/zfound, 437.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.83 (d,J=2.5, 1H), 8.18-8.03 (m, 2H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H),7.57-7.51 (m, 1H), 7.41-7.32 (m, 3H), 6.87-6.82 (m, 1H), 2.93-2.81 (m,4H), 1.46-1.36 (m, 6H).

Example 375

2-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(morphilinosulfonyl)phenyl)boronicacid in Step B. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₃S, 438.12; m/zfound, 439.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.69 (s, 1H), 8.79 (d,J=2.6, 1H), 8.17-8.06 (m, 2H), 7.71-7.61 (m, 2H), 7.61-7.53 (m, 1H),7.44-7.33 (m, 3H), 6.80-6.74 (m, 1H), 3.54-3.45 (m, 4H), 2.94-2.83 (m,4H).

Example 376

racemic3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide

To a mixture of2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-pyrrolo[2,3-b]pyrazine(32 mg, 0.09 mmol), racemic2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide (38 mg, 0.11mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (6 mg, 0.007 mmol) in a microwave vial wereadded acetonitrile (2.0 mL) and sat. NaHCO₃ (2.0 mL). The mixture wassparged with nitrogen for 5 min and then the vial capped and heated at110° Celsius for 90 min. After cooling, the reaction mixture was dilutedwith ethyl acetate (50 mL) and washed with water (25 mL) and brine (25mL). The organic layer was dried (Na₂SO₄) and concentrated to dryness.The crude product was purified by HPLC to give the title compound (28mg, 64%). MS (ESI): mass calcd. C₂₁H₁₆F₄N₄O₂S, 464.09; m/z found, 465.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, 1H), 8.47 (s, 1H), 8.27-8.17(m, 1H), 7.75-7.41 (m, 5H), 7.40-7.32 (m, 2H), 7.20 (d, J=12.6, 1H),6.74-6.67 (m, 1H), 4.12-3.94 (m, 1H), 1.39-1.19 (m, 3H).

Example 377

2-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazineStep A:2-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(methylthio)phenyl)boronic acid inStep B. MS (ESI): mass calcd. for C₁₉H₁₄FN₃S, 335.09; m/z found, 336.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.81 (d, J=2.5, 1H),8.11-8.01 (m, 1H), 7.69-7.63 (m, 1H), 7.44-7.19 (m, 6H), 6.87-6.82 (m,1H), 2.41 (s, 3H).

Step B

To a 10 mL round bottomed flask under nitrogen at rt were added2-[3-fluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine(32 mg, 0.07 mmol), m-CPBA (0.33 mg, 0.19 mmol) and DCM (1 mL). Themixture was stirred at rt for 2 hours. An additional 0.5 equivalents ofmCPBA was added at this time and the reaction stirred an additional 1hour. The reaction was then poured into sat. NaHCO₃ and extracted withDCM (×2). The solvent was then removed and the crude product purified byHPLC to give the title compound (12 mg, 35%). MS (ESI): mass calcd. forC₁₉H₁₄FN₃O₂S, 481.08; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.48 (s, 1H), 8.82 (s, 1H), 8.27 (d, J=8.0, 1H), 8.18-8.09 (m, 1H),7.77-7.67 (m, 2H), 7.66-7.57 (m, 1H), 7.48-7.36 (m, 3H), 6.89-6.83 (m,1H), 2.76 (s, 3H).

Example 378

3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using(R)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): masscalcd. C₂₁H₁₉FN₄O₃S, 426.12; m/z found, 427.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.40 (s, 1H), 8.74 (d, J=2.7, 1H), 8.60 (s, 1H), 8.29-8.20 (m,1H), 7.83-7.74 (m, 1H), 7.71-7.62 (m, 2H), 7.61-7.50 (m, 1H), 7.47-7.36(m, 2H), 7.35-7.16 (m, 1H), 5.50 (s, 1H), 3.65-3.49 (m, 1H), 3.48-3.28(m, 2H), 2.16-1.94 (m, 1H), 1.04 (d, J=6.6, 3H).

Example 379

3′-Fluoro-N-methyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using 2-bromo-N-methylbenzenesulfonamide. MS(ESI): mass calcd. C₁₉H₁₅FN₄O₂S, 382.09; m/z found, 383.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.67 (d, J=2.2, 1H), 8.29-8.18 (m, 1H),8.03-7.83 (m, 1H), 7.71-7.55 (m, 3H), 7.47-7.29 (m, 3H), 6.83-6.73 (m,1H), 4.85 (s, 1H), 2.56 (d, J=5.2, 3H).

Example 380

3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 376 using(S)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): masscalcd. C₂₁H₁₉FN₄O₃S, 426.12; m/z found, 427.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.40 (s, 1H), 8.74 (d, J=2.7, 1H), 8.60 (s, 1H), 8.29-8.20 (m,1H), 7.83-7.74 (m, 1H), 7.71-7.62 (m, 2H), 7.61-7.50 (m, 1H), 7.47-7.36(m, 2H), 7.35-7.16 (m, 1H), 5.50 (s, 1H), 3.65-3.49 (m, 1H), 3.48-3.28(m, 2H), 2.16-1.94 (m, 1H), 1.04 (d, J=6.6, 3H).

Example 381

1-{[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-amineStep A: tert-Butyl(1-((3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)-[1,1′-biphenyl]-2-yl)-sulfonyl)piperidin-4-yl)carbamate

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-4-yl)carbamate. MS(ESI): mass calcd. for C₂₈H₃₀FN₅O₄S, 551.20; m/z found, 552.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.81 (d, J=2.4, 1H), 8.18-8.04 (m,2H), 7.69-7.59 (m, 2H), 7.60-7.48 (m, 1H), 7.48-7.30 (m, 4H), 6.85 (dd,J=3.7, 1.9, 1H), 4.44 (d, J=8.2, 1H), 3.79 (d, J=13.2, 1H), 3.49-3.27(m, 3H), 2.91 (t, J=11.7, 1H), 2.47 (t, J=12.2, 2H), 1.98 (d, J=13.4,1H), 1.79 (d, J=11.8, 2H), 1.42 (d, J=9.5, 12H), 1.31-1.10 (m, 3H).

Step B

The title compound was prepared as described in the preparation ofExample 247 using tert-butyl(1-((3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)carbamate.MS (ESI): mass calcd. for C₂₃H₂₂FN₅O₂S, 451.15; m/z found, 452.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 9.66 (s, 1H), 8.82 (d, J=2.5, 1H), 8.20-8.04(m, 2H), 7.69 (d, J=3.7, 1H), 7.66-7.59 (m, 1H), 7.58-7.51 (m, 1H),7.42-7.32 (m, 3H), 6.83 (d, J=3.7, 1H), 3.43-3.30 (m, 2H), 2.70-2.59 (m,1H), 2.55-2.40 (m, 2H), 1.75-1.65 (m, 2H), 1.56 (br s, 2H), 1.24-1.07(m, 2H).

Example 382

2-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using 4-((2-bromophenyl)sulfonyl)thiomorpholine1,1-dioxide. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₄S₂, 486.08; m/z found,487.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.83 (d, J=2.5,1H), 8.22-8.11 (m, 2H), 7.75-7.65 (m, 2H), 7.64-7.55 (m, 1H), 7.43-7.37(m, 1H), 7.34-7.21 (m, 2H), 6.88-6.80 (m, 1H), 3.45-3.26 (m, 4H),3.09-2.94 (m, 4H).

Example 383

2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (5-fluoro-2-(methylthio)phenyl)boronicacid in Step B. MS (ESI): mass calcd. for C₁₉H₁₃F₂N₃S, 353.08; m/zfound, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.82 (d,J=2.6, 1H), 8.14-8.05 (m, 1H), 7.70-7.63 (m, 1H), 7.41-7.28 (m, 3H),7.13-7.01 (m, 2H), 6.87-6.80 (m, 1H), 2.36 (s, 3H).

Example 384

2-[2′-(Ethylsulfanyl)-3-fluorobiphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(ethylthio)phenyl)boronic acid in StepB. MS (ESI): mass calcd. for C₂₀H₁₆FN₃S, 349.10; m/z found, 350.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.83 (d, J=2.6, 1H),8.11-8.02 (m, 1H), 7.69-7.63 (m, 1H), 7.44-7.21 (m, 6H), 6.86-6.81 (m,1H), 2.85 (q, J=7.4, 2H), 1.26 (t, J=7.4, 3H).

Example 385

7-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand 1-bromo-2-(methylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₀H₁₇FN₂O₃S, 384.09; m/z found, 385.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.27-8.24 (m, 1H), 7.99-7.93 (m, 1H), 7.71-7.65 (m, 1H), 7.63-7.57 (m,1H), 7.47 (m, 1H), 7.41-7.38 (m, 1H), 7.33-7.27 (m, 3H), 4.32-4.24 (m,2H), 3.67-3.59 (m, 2H), 2.76 (s, 3H).

Example 386

7-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand 1-((2-bromophenyl)sulfonyl)piperidine. MS (ESI): mass calcd. forC₂₄H₂₄FN₃O₃S, 453.15; m/z found, 454.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.07-8.03 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.67 (m, 2H), 7.65-7.55 (m,2H), 7.42-7.39 (m, 1H), 7.36-7.30 (m, 2H), 4.41-4.32 (m, 2H), 3.74-3.71(m, 2H), 2.91-2.79 (m, 4H), 1.49-1.37 (m, 6H).

Example 387

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand 2-bromobenzenesulfonamide. MS (ESI): mass calcd. for C₁₉H₁₆FN₃O₃S,385.09; m/z found, 386.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.14-8.11 (m,1H), 7.80 (d, J=1.0, 1H), 7.73-7.71 (m, 1H), 7.68-7.62 (m, 1H),7.61-7.52 (m, 2H), 7.39-7.31 (m, 3H), 4.40-4.34 (m, 2H), 3.75-3.69 (m,2H).

Example 388

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₂FN₃O₄S, 443.13; m/z found, 444.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.15-8.12 (m, 1H), 7.80 (m, 1H), 7.72 (d, J=1.3, 1H),7.69-7.64 (m, 1H), 7.62-7.52 (m, 2H), 7.40-7.33 (m, 3H), 4.37 (t, J=4.6,2H), 3.76-3.69 (m, 2H), 3.43-3.36 (m, 1H), 3.30-3.26 (m, 1H), 3.24-3.16(m, 1H), 1.04-1.01 (m, 3H).

Example 389

1-{[4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-amine

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd.for C₂₄H₂₅FN₄O₃S, 468.16; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.09-8.05 (m, 1H), 7.83 (d, J=1.1, 1H), 7.75-7.68 (m, 2H),7.66-7.55 (m, 2H), 7.43-7.39 (m, 1H), 7.34-7.26 (m, 2H), 4.39-4.35 (m,2H), 3.76-3.68 (m, 2H), 3.47 (d, J=13.4, 2H), 3.21-3.11 (m, 1H),2.60-2.50 (m, 2H), 1.96-1.87 (m, 2H), 1.56-1.43 (m, 2H).

Example 390

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₂FN₃O₄S, 443.13; m/z found, 444.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.16-8.10 (m, 1H), 7.82-7.79 (m, 1H), 7.74-7.71 (m,1H), 7.70-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.46 (m, 1H), 7.40-7.33(m, 3H), 4.40-4.36 (m, 2H), 3.75-3.69 (m, 2H), 3.48-3.33 (m, 2H),3.24-3.16 (m, 1H), 1.05-1.01 (m, 3H).

Example 391

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineand 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. forC₂₃H₂₄FN₃O₃S, 441.15; m/z found, 442.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.03-8.00 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.65 (m, 2H), 7.62-7.55 (m,2H), 7.40-7.36 (m, 1H), 7.31 (s, 1H), 7.30-7.28 (m, 1H), 4.39-4.35 (m,2H), 3.74-3.70 (m, 2H), 2.99 (q, J=7.1, 4H), 1.01 (t, J=7.1, 6H).

Example 392

7-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazineStep A:7-(4-Chloro-2-fluorophenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

Prepared in a manner similar to that found in Example 1 using of7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine with(4-chloro-2-fluorophenyl)boronic acid. ¹H NMR (400 MHz, CDCl₃) δ 7.84(m, 1H), 7.35-7.28 (m, 1H), 7.20-7.14 (m, 3H), 4.29-4.25 (m, 2H),3.64-3.58 (m, 2H).

Step B:7-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

Into a 100 mL flask were added7-(4-chloro-2-fluorophenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(1.25 g, 4.72 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5 g, 5.9mmol), KOAc (1.39 g, 14.2 mmol),Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),186 g, 0.236 mmol), and a stir bar. The flask was sealed with a rubberseptum and sparged with N₂. The flask was charged with freshly sparged1,4-dioxane (25 mL) and heated at 80° Celsius for 16 hours. The reactionwas cooled to rt and concentrated to dryness. The crude product waspurified by FCC to give7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(1.208 g, 71%). ¹H NMR (500 MHz, CDCl₃) δ 7.86-7.84 (m, 1H), 7.61-7.59(m, 1H), 7.56-7.53 (m, 1H), 7.38 (m, 1H), 7.27-7.24 (m, 1H), 4.27-4.22(m, 2H), 3.61-3.58 (m, 2H), 2.09 (s, 1H), 1.35 (s, 12H).

Step C

7-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-3,4-dihydro-2H-pyrido[3,2-b]-b][1,4]oxazine.Prepared in a manner similar to that found in Example 444 using7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b]-b][1,4]oxazinewith 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI):mass calcd. for C₂₃H₂₂FN₃O₅S₂, 503.10; m/z found, 504.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.16-8.13 (m, 1H), 7.85-7.83 (m, 1H), 7.78-7.72 (m,2H), 7.69-7.60 (m, 2H), 7.45-7.41 (m, 1H), 7.37-7.30 (m, 2H), 4.41-4.35(m, 2H), 3.76-3.68 (m, 2H), 3.38-3.33 (m, 4H), 3.06-2.98 (m, 4H).

Example 393

N-tert-Butyl-4′-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (ESI): masscalcd. for C₂₃H₂₄FN₃O₃S, 441.15; m/z found, 442.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.15-8.12 (m, 1H), 7.80 (d, J=0.9, 1H), 7.72-7.69 (m, 1H),7.68-7.62 (m, 1H), 7.60-7.54 (m, 2H), 7.39-7.33 (m, 3H), 4.42-4.33 (m,2H), 3.75-3.69 (m, 2H), 1.09 (s, 9H).

Example 394

2-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]-5-(trifluoromethyl)pyridin-3-yl}phenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-(isopropylthio)-5-(trifluoromethyl)pyridine-3-yl)boronic acid in StepB. MS (ESI): mass calcd. for C₂₁H₁₆F₄N₄S, 432.10; m/z found, 433.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.83 (d, J=2.6, 1H),8.74-8.68 (m, 1H), 8.19-8.10 (m, 1H), 7.71-7.66 (m, 1H), 7.62 (d, J=1.9,1H), 7.42-7.37 (m, 1H), 7.33 (dd, J=1.7, 11.52, 1H), 6.87-6.82 (m, 1H),4.19-4.03 (m, 1H), 1.40 (d, J=6.8, 6H).

Example 395

5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amineStep A: 3-Bromo-2-(isopropylthio)pyridine

3-Bromopyridine-2-thiol (500 mg, 2.63 mmol) was added drop-wise to asuspension of sodium hydride in mineral oil (60%, 126 mg, 3.16 mmol) inDMF (5.0 mL) at 0° Celsius. The mixture was then stirred at 0° Celsiusfor 30 min followed by removal of the ice bath and stirring at rt for anadditional 30 min. 2-Iodopropane (537 mg, 3.16 mmol) was then added andthe reaction stirred at 60° Celsius for 18 hours. The reaction wascooled to rt, carefully diluted with water (100 mL), and extracted withethyl acetate (2×100 mL). The combined organic extracts were dried withNa₂SO₄, filtered and concentrated to dryness. The crude product waspurified by FCC giving 453 mg (74%) of the target thioether. MS (ESI):mass calcd. for C₈H₁₀BrNS, 230.97; m/z found, 232.1 [M+H]⁺.

Step B: 3-Bromo-2-(isopropylsulfonyl)pyridine

3-Bromo-2-(isopropylthio)pyridine (100 mg, 0.43 mmol) was dissolved inDCM (6.0 mL) and m-CPBA (198 mg, 1.15 mmol) added. The reaction wasstirred for 1.5 hours, and then treated with additional m-CPBA (100 mg,0.058 mmol). Once complete conversion was achieved, the mixture waspoured into sat. NaHCO₃ (50 mL) and extracted with DCM (2×50 mL). Thecombined extracts were concentrated to dryness and the crude product(112 mg, 98%) was used in next step without further purification.

Step C

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 3-bromo-2-(isopropylsulfonyl)pyridine yielding 52 mg (88%) of thetitle compound. MS (ESI): mass calcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/zfound, 373.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.69 (dd, J=4.6, 1.7,1H), 8.60 (dd, J=2.1, 1.5, 1H), 8.10 (d, J=1.5, 1H), 8.08-7.98 (m, 1H),7.81 (dd, J=7.8, 1.6, 1H), 7.58 (dd, J=7.8, 4.6, 1H), 7.38 (dd, J=8.0,1.8, 1H), 7.32 (dd, J=11.7, 1.7, 1H), 4.71 (s, 2H), 4.19 (hept, J=6.8,1H), 1.31 (d, J=6.9, 6H).

Example 396

5-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]pyridin-3-yl}phenyl)pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 3-bromo-2-(isopropylthio)pyridine. MS (ESI): mass calcd. forC₁₈H₁₇FN₄S, 340.12; m/z found, 341.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.62-8.57 (m, 1H), 8.49-8.43 (m, 1H), 8.12 (d, J=1.5, 1H), 8.04-7.93 (m,1H), 7.45-7.39 (m, 1H), 7.34-7.30 (m, 1H), 7.29-7.22 (m, 1H), 7.11-7.03(m, 1H), 4.69 (s, 2H), 4.17-4.00 (m, 1H), 1.37 (d, J=6.8, 6H).

Example 397

2-{2-Fluoro-4-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-((2,2,2-trifluoroethoxy)pyridine-3-yl)boronic acid in Step B. MS(ESI): mass calcd. for C₁₉H₁₂F₄N₄O, 388.09; m/z found, 389.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.83 (d, J=2.5, 1H), 8.21-8.16 (m,1H), 8.16-8.07 (m, 1H), 7.82-7.76 (m, 1H), 7.71-7.64 (m, 1H), 7.57-7.52(m, 1H), 7.51-7.44 (m, 1H), 7.16-7.09 (m, 1H), 6.87-6.82 (m, 1H),4.95-4.79 (m, 2H).

Example 398

2-{2-Fluoro-4-[2-(2-methylpropoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-isobutoxypyridin-3-yl)boronic acid inStep B. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O, 362.15; m/z found, 363.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.84 (d, J=2.5, 1H),8.23-8.15 (m, 1H), 8.14-8.04 (m, 1H), 7.74-7.65 (m, 2H), 7.59-7.48 (m,2H), 7.03-6.96 (m, 1H), 6.88-6.81 (m, 1H), 4.17 (d, J=6.6, 2H),2.33-1.99 (m, 1H), 1.02 (d, J=6.7, 6H).

Example 399

2-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-isopropoxypyridin-3-yl)boronic acid inStep B. MS (ESI): mass calcd. for C₂₀H₁₇FN₄O, 348.14; m/z found, 349.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 1H), 8.83 (d, J=2.5, 1H),8.17 (dd, J=1.9, 4.9, 1H), 8.11-8.01 (m, 1H), 7.72-7.64 (m, 2H),7.57-7.46 (m, 2H), 6.96 (dd, J=5.0, 7.3, 1H), 6.87-6.80 (m, 1H),5.52-5.37 (m, 1H), 1.38 (d, J=6.2, 6H).

Example 400

2-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-(cyclopropylmethoxy)pyridin-3-yl)boronic acid in Step B. MS (ESI):mass calcd. for C₂₁H₁₇FN₄O, 360.14; m/z found, 361.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 9.28 (s, 1H), 8.83 (d, J=2.5, 1H), 8.19-8.14 (m, 1H),8.13-8.04 (m, 1H), 7.74-7.64 (m, 2H), 7.61-7.53 (m, 2H), 6.99 (dd,J=5.0, 7.4, 1H), 6.84 (dd, J=1.9, 3.7, 1H), 4.25 (d, J=7.0, 2H),1.39-1.23 (m, 1H), 0.67-0.57 (m, 2H), 0.41-0.31 (m, 2H).

Example 401

5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-isopropoxypyridin-3-yl)boronic acidand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₈H₁₇FN₄O, 324.14; m/z found, 325.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.63-8.57 (m, 1H), 8.18-8.13 (m, 1H), 8.12 (d, J=1.4, 1H),7.99-7.90 (m, 1H), 7.69-7.62 (m, 1H), 7.58-7.41 (m, 2H), 6.98-6.91 (m,1H), 5.49-5.35 (m, 1H), 4.68 (s, 2H), 1.37 (d, J=6.2, 6H).

Example 402

5-{4-[2-(Cyclopentyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(cyclopentyloxy)pyridin-3-yl)boronicacid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.62-8.58 (m, 1H), 8.19-8.15 (m, 1H), 8.12 (d, J=1.5, 1H),8.00-7.90 (m, 1H), 7.69-7.63 (m, 1H), 7.48-7.40 (m, 2H), 6.98-6.92 (m,1H), 5.59-5.50 (m, 1H), 4.68 (s, 2H), 2.03-1.89 (m, 2H), 1.89-1.70 (m,4H), 1.71-1.55 (m, 2H).

Example 403

5-{4-[2-(Cyclohexyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(cyclohexyloxy)pyridin-3-yl)boronicacid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI):mass calcd. for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.64-8.57 (m, 1H), 8.18-8.10 (m, 2H), 8.00-7.92 (m, 1H),7.70-7.63 (m, 1H), 7.52-7.43 (m, 2H), 6.94 (dd, J=5.0, 7.4, 1H),5.26-5.16 (m, 1H), 4.66 (s, 2H), 2.05-1.91 (m, 2H), 1.82-1.68 (m, 2H),1.66-1.24 (m, 6H).

5-[2-Fluoro-4-(2-methoxypyridin-3-yl)phenyl]pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(methoxy)pyridin-3-yl)boronic acid and5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₆H₁₃FN₄O, 296.11; m/z found, 297.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.62-8.56 (m, 1H), 8.19 (dd, J=1.9, 5.0, 1H), 8.12 (d, J=1.5,1H), 8.01-7.94 (m, 1H), 7.70-7.65 (m, 1H), 7.48-7.41 (m, 2H), 7.00 (dd,J=5.0, 7.31, 1H), 4.66 (s, 2H), 4.00 (s, 3H).

Example 405

5-{4-[2-(Cyclobutyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-(cyclobutoxy)pyridin-3-yl)boronic acidand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₉H₁₇FN₄O, 336.14; m/z found, 337.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.63-8.57 (m, 1H), 8.17-8.10 (m, 2H), 8.01-7.92 (m, 1H), 7.66(dd, J=1.9, 7.4, 1H), 7.52-7.43 (m, 2H), 7.00-6.93 (m, 1H), 5.38-5.22(m, 1H), 4.67 (s, 2H), 2.57-2.37 (m, 2H), 2.26-2.05 (m, 2H), 1.90-1.61(m, 2H).

Example 406

tert-Butyl3-[({3-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)methyl]pyrrolidine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 369 using tert-butyl3-(((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)methyl)pyrrolidine-1-carboxylateand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₂₅H₂₈FN₅O₃, 465.22; m/z found, 466.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.63-8.58 (m, 1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H),7.73-7.64 (m, 1H), 7.48-7.36 (m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H),4.47-4.22 (m, 2H), 3.68-3.26 (m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m,1H), 2.14-1.98 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (s, 9H).

Example 407

5-{2-Fluoro-4-[2-(pyrrolidin-3-ylmethoxy)pyridin-3-yl]phenyl}pyrazin-2-amineStep A: Tert-butyl3-(((3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridine-2-yl)oxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand tert-butyl3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate yieldingthe title compound (47 mg, 54%). MS (ESI): mass calcd. for C₂₅H₂₈FN₅O₃,465.22; m/z found, 466.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.63-8.58 (m,1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H), 7.73-7.64 (m, 1H), 7.48-7.36(m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H), 4.47-4.22 (m, 2H), 3.68-3.26(m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m, 1H), 2.14-1.98 (m, 1H),1.84-1.68 (m, 1H), 1.44 (s, 9H).

Step B

The title compound was prepared as described in the preparation ofExample 249 using tert-butyl3-(((3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridine-2-yl)oxy)methyl)pyrrolidine-1-carboxylateto give the title compound (15 mg, 41%). MS (ESI): mass calcd. forC₂₀H₂₀FN₅O, 365.17; m/z found, 366.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.63-8.57 (m, 1H), 8.20-8.13 (m, 1H), 8.12 (d, J=1.5, 1H), 8.02-7.93 (m,1H), 7.72-7.65 (m, 1H), 7.49-7.38 (m, 2H), 7.03-6.96 (m, 1H), 4.69 (s,2H), 4.40-4.20 (m, 2H), 3.09 (dd, J=11.2, 7.7, 1H), 3.04-2.83 (m, 2H),2.76 (dd, J=11.2, 6.1, 1H), 2.66-2.49 (m, 1H), 2.06-1.89 (m, 1H),1.61-1.49 (m, 2H).

Example 408

5-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}pyrimidin-2-amine

To a microwave vial the following were added5-(4-chloro-2-fluorophenyl)-pyrimidin-2-amine (50 mg, 0.22 mmol),(2-isopropoxypyridin-3-yl)boronic acid (51 mg, 0.28 mmol) and X-Phosprecatalyst (4 mg, 0.005 mmol). The vial was flushed with nitrogen andthen THF (0.5 mL) and 0.5 M K₃PO₄ (0.9 mL) were added. Both THF and theK₃PO₄ solution were sparged separately for 30 min prior to use. Theresulting biphasic mixture was stirred at rt overnight. The reactionmixture was then poured into sat. NaHCO₃ (50 mL) and extracted withethyl acetate (2×50 mL). The combined organic extracts were washed withwater (1×50 mL) and brine (1×50 mL), dried (Na₂SO₄) and concentrated todryness. The crude product was purified by HPLC to give the titlecompound (35 mg, 48%). MS (ESI): mass calcd. for C₁₈H₁₇FN₄O, 324.14; m/zfound, 325.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=1.4, 2H),8.21-8.13 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.36 (m, 3H), 6.99-6.91 (m,1H), 5.51-5.37 (m, 1H), 5.15 (s, 2H), 1.38 (d, J=6.2, 6H).

Example 409

5-[4-(2-Aminopyridin-3-yl)-2-fluorophenyl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 3-bromopyridin-2-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₅H₁₂FN₅, 281.11; m/z found, 282.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.64-8.54 (m, 1H), 8.00-7.89 (m, 1H), 7.74-7.64(m, 1H), 7.46-7.36 (m, 1H), 7.09-7.03 (m, 1H).

Example 410

4′-(5-amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared in manner similar to that described inExample 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamideand3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.73 (d, J=2.1, 1H), 8.16 (dd, J=7.9, 1.4,1H), 7.93 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.45-7.28 (m, 3H),3.47-3.36 (m, 1H), 3.34-3.18 (m, 2H), 1.03 (d, J=6.6, 3H).

Example 411

3-Amino-6-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared in manner similar to that described inExample 88 using 1-bromo-2-(cyclopropylsulfonyl)benzene and3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₀H₁₅FN₄O₂S, 394.09; m/z found, 395.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.84 (d, J=1.8, 1H), 8.14 (dd, J=8.0, 1.4,1H), 8.01 (m, 1H), 7.66 (m, 1H), 7.58 (m, 1H), 7.39-7.35 (m, 3H), 5.34(s, 2H), 2.13-2.05 (m, 1H), 1.13-1.06 (m, 2H), 0.88-0.82 (m, 2H).

Example 412

4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared in manner similar to that described inExample 88 using (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamideand3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=1.6, 1H), 8.18 (dd, J=7.9, 1.4,1H), 8.01 (m, 1H), 7.63 (m, 1H), 7.56 (m, 1H), 7.40-7.32 (m, 3H), 5.43(s, 2H), 4.46-4.36 (m, 1H), 3.55-3.46 (m, 1H), 3.43-3.28 (m, 2H), 1.76(t, J=5.7, 1H), 0.99 (d, J=6.6, 3H).

Example 413

4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

The title compound was prepared in manner similar to that described inExample 88 using 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide and3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₁₉H₁₆FN₅O₃S, 413.10; m/z found, 414.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.81 (d, J=1.8, 1H), 8.17 (dd, J=8.0, 1.4,1H), 8.02 (m, 1H), 7.64 (m, 1H), 7.56 (m, 1H), 7.40-7.31 (m, 3H), 5.38(s, 2H), 4.35 (s, 1H), 3.64-3.58 (m, 2H), 2.95-2.87 (m, 2H), 1.64 (t,J=5.2, 1H).

Example 414

3-Amino-6-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 4-((2-bromophenyl)sulfonyl)piperazin-2-one and3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₁H₁₇FN₆O₃S, 452.11; m/z found, 453.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.65 (d, J=2.1, 1H), 8.05 (dd, J=8.1, 1.3,1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.36 (dd, J=7.6, 1.3,1H), 7.26-7.17 (m, 2H), 3.29 (s, 2H), 3.04 (s, 4H).

Example 415

4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide and3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.75 (d, J=2.1, 1H), 8.09 (dd, J=8.0, 1.3,1H), 7.95 (m, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.43 (dd, J=7.6, 1.4,1H), 7.39-7.31 (m, 2H), 3.74-3.62 (m, 1H), 2.80-2.67 (m, 2H), 1.07 (d,J=6.3, 3H).

Example 416

3-Amino-6-[3-fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using (2-bromophenyl)(morpholino)methanone and3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₂₂H₁₈FN₅O₂, 403.14; m/z found, 404.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 7.45 (d, J=2.1, 1H), 6.71 (m, 1H), 6.32-6.21(m, 3H), 6.17-6.10 (m, 2H), 6.07 (dd, J=12.4, 1.8, 1H), 2.40-2.22 (m,3H), 2.13-2.03 (m, 2H), 1.86-1.77 (m, 1H), 1.62-1.49 (m, 2H).

Example 417

4′-(6-Aminopyridazin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 6-chloropyridazin-3-amine. MS (ESI): mass calcd. for C₂₀H₂₁FN₄O₂S,400.14; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26-8.22 (m,1H), 8.16-8.13 (m, 1H), 7.91-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.63-7.56(m, 2H), 7.44-7.37 (m, 3H), 1.09 (s, 9H).

Example 418

N-tert-Butyl-3′-fluoro-4′-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 2-bromo-7H-pyrrolo[2,3-d]pyrimidine. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ9.31 (s, 1H), 8.82 (s, 1H), 8.15 (m, 1H), 7.90 (d, J=3.6, 1H), 7.68 (d,J=7.5, 1H), 7.63 (d, J=6.3, 1H), 7.50 (s, 1H), 7.42 (d, J=7.1, 1H), 7.02(d, J=3.6, 1H), 6.66 (d, J=3.6, 1H), 1.12 (s, 9H).

Example 419

N-tert-Butyl-3′-fluoro-4′-(1,8-naphthyridin-3-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 444 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 3-bromo-1,8-naphthyridine. MS (ESI): mass calcd. for C₂₄H₂₂FN₃O₂S,435.14; m/z found, 436.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.46 (s, 1H),9.23 (s, 1H), 8.89 (s, 1H), 8.85 (d, J=7.2, 1H), 8.18-8.14 (m, 1H),7.94-7.90 (m, 1H), 7.80 (m, 1H), 7.70-7.65 (m, 1H), 7.62-7.57 (m, 1H),7.49-7.40 (m, 3H), 1.11 (s, 9H).

Example 420

N-tert-Butyl-3′-fluoro-4′-quinoxalin-6-ylbiphenyl-2-sulfonamide Step A:4′-Bromo-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

1-Bromo-2-fluoro-4-iodobenzene (117 mg, 0.389 mmol) and(2-(N-(tert-butyl)sulfamoyl)phenyl) boronic acid (100 mg, 0.389 mmol)were added to a 5 mL sealable vial equipped with a stir bar. 1,4-Dioxane(1 mL) and 2 M Na₂CO₃ (1 mL) solution were added. Argon was bubbledthrough the solvent while it was rapidly stirred for 10 min thenPd(dppf)Cl₂.CH₂Cl₂ (14 mg, 0.019 mmol) was added. The mixture was thenstirred for 15 hours at 80° Celsius under an argon atmosphere. Thereaction was diluted with 2 mL of ethyl acetate and 2 mL of water andthe aqueous layer was extracted with ethyl acetate (3×10 mL). Thecombined organic extracts were then dried with Na₂SO₄ and concentratedto dryness. The crude product was purified by FCC to give the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ 8.20-8.15 (dd, J=7.9, 1.4, 1H),7.64-7.59 (dd, J=8.2, 7.1, 1H), 7.60-7.55 (m, 1H), 7.54-7.49 (m, 1H),7.31-7.27 (m, 2H), 7.21-7.16 (dd, J=8.5, 2.2, 1H), 3.65 (s, 1H), 1.07(s, 9H).

Step B: N-tert-Butyl-3′-fluoro-4′-quinoxalin-6-ylbiphenyl-2-sulfonamide

4′-Bromo-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (30 mg,0.078 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (12 mg, 0.085mmol) were added to a 5 mL sealable vial equipped with a stir bar.Dioxane (0.2 mL) and 2 M Na₂CO₃ (0.2 mL) were added. Argon was bubbledthrough the solvent while it was rapidly stirred for 10 min thenPd(dppf)Cl₂.CH₂Cl₂ (3 mg, 0.004 mmol) was added, and the mixture heatedfor 15 hours at 80° Celsius under an argon atmosphere. The reaction wasdiluted with 2 mL of ethyl acetate and 2 mL of water and the aqueouslayer was extracted with ethyl acetate (3×10 mL). The combined organicextracts were then dried with Na₂SO₄ and concentrated to dryness. Thecrude product was purified by HPLC to give the title compound. MS (ESI):mass calcd. for C₂₄H₂₂FN₃O₂S, 435.14; m/z found, 436.4 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.93-8.91 (d, J=1.8, 1H), 8.91-8.89 (d, J=1.8, 1H),8.37-8.34 (m, 1H), 8.24-8.22 (m, 1H), 8.22-8.20 (m, 1H), 8.09-8.04 (m,1H), 7.71-7.66 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.52 (m, 1H), 7.51-7.44(dd, J=7.9, 1.8, 1H), 7.44-7.40 (dd, J=11.3, 1.7, 1H), 7.40-7.36 (dd,J=7.5, 1.4, 1H), 3.74 (s, 1H), 1.10 (s, 9H).

Example 421

N-tert-Butyl-3′-fluoro-4′-(1H-indol-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylatein Step B. After work up, the Boc group was then removed by treatmentwith trifluoroacetic acid (0.3 mL) in dichloromethane (1 mL) at rtfollowed by concentration and purification by HPLC to give the titlecompound. MS (ESI): mass calcd. for C₂₄H₂₃FN₂O₂S, 422.15; m/z found,423.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (s, 1H), 8.23-8.17 (dd,J=8.0, 1.3, 1H), 7.91-7.85 (m, 1H), 7.63-7.56 (m, 2H), 7.55-7.49 (m,2H), 7.48-7.43 (m, 1H), 7.42-7.36 (m, 2H), 7.36-7.31 (dd, J=11.3, 1.8,1H), 7.31-7.27 (dd, J=3.2, 2.4, 1H), 6.67-6.61 (m, 1H), 3.72 (s, 1H),1.06 (s, 9H).

Example 422

4′-(1H-Benzimidazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole inStep B. MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₂S, 423.14; m/z found, 424.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.32-9.21 (d, J=6.0, 1H), 8.18-8.12(dd, J=8.0, 1.3, 1H), 8.04 (s, 1H), 7.96-7.89 (m, 1H), 7.89-7.82 (m,1H), 7.69-7.55 (m, 3H), 7.45-7.33 (m, 3H), 1.11 (s, 9H).

Example 423

4′-(1H-Benzimidazol-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using (2-(N-methylsulfamoyl)phenyl)boronic acid in Step Aand 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazolein Step B. MS (ESI): mass calcd. for C₂₀H₁₆FN₃O₂S, 381.09; m/z found,382.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.35 (s, 1H), 8.06 (s, 1H),8.05-8.03 (dd, J=8.0, 1.3, 1H), 7.96-7.92 (m, 1H), 7.91-7.86 (m, 1H),7.72-7.67 (m, 1H), 7.65-7.60 (m, 2H), 7.46-7.43 (dd, J=7.5, 1.4, 1H),7.38-7.32 (m, 2H), 2.50 (s, 3H).

Example 424

4′-(1,3-Benzothiazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzo[d]thiazole in StepB. MS (ESI): mass calcd. for C₂₃H₂₁FN₂O₂S₂, 440.10; m/z found, 441.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 8.39-8.35 (m, 1H),8.24-8.19 (dd, J=8.0, 1.3, 1H), 8.10-8.05 (dd, J=8.4, 0.6, 1H),7.75-7.69 (m, 1H), 7.65-7.62 (m, 1H), 7.62-7.58 (m, 1H), 7.57-7.51 (m,1H), 7.45-7.42 (dd, J=7.8, 1.8, 1H), 7.41-7.38 (dd, J=4.1, 1.5, 1H),7.38-7.36 (d, J=1.6, 1H), 3.73 (s, 1H), 1.08 (s, 9H).

Example 425

N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[3,2-b]pyridin-6-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridinein Step B. MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₂S, 423.14; m/z found,424.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.87-8.81 (m, 1H), 8.77-8.70 (d,J=1.5, 1H), 8.20-8.17 (d, J=3.3, 1H), 8.17-8.12 (dd, J=8.0, 1.3, 1H),7.78-7.71 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.47-7.44 (dd,J=4.9, 1.5, 1H), 7.44 (s, 1H), 7.43-7.40 (dd, J=7.5, 1.4, 1H), 6.95-6.89(dd, J=3.2, 0.9, 1H), 1.12 (s, 9H).

Example 426

3′-Fluoro-N-methyl-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 420 using (2-(N-methylsulfamoyl)phenyl)boronic acid in Step Aand5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinein Step B. MS (ESI): mass calcd. for C₂₀H₁₆FN₃O₂S, 381.09; m/z found,382.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.49 (s, 1H), 8.46-8.37 (m, 1H),8.13-7.97 (dd, J=7.9, 1.3, 1H), 7.74-7.66 (m, 1H), 7.66-7.57 (m, 2H),7.57-7.52 (d, J=3.5, 1H), 7.46-7.40 (dd, J=7.7, 1.4, 1H), 7.38-7.30 (m,2H), 6.72-6.63 (d, J=3.5, 1H), 2.48 (s, 3H).

Example 427

4′-(5-Aminopyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

N-(tert-Butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide(37 mg, 0.085 mmol) and 6-bromopyridin-3-amine (22 mg, 0.13 mmol) wereadded to a 5 mL sealable vial equipped with a stir bar. 1,4-Dioxane (0.2mL) and 2 M Na₂CO₃ (0.2 mL) were added. Argon was bubbled through thesolvent while it was rapidly stirred for 10 min then Pd(dppf)Cl₂.CH₂Cl₂(3 mg, 0.004 mmol) was added, and the mixture stirred for 15 hours at80° Celsius under an argon atmosphere. The reaction was diluted with 2mL of ethyl acetate and 2 mL of water and the aqueous layer wasextracted with ethyl acetate (3×10 mL). The combined organic extractswere then dried with Na₂SO₄ and concentrated to dryness. The crudeproduct was purified by HPLC to give the title compound. MS (ESI): masscalcd. for C₂₁H₂₂FN₃O₂S, 399.14; m/z found, 400.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.66 (s, 1H), 8.25-8.16 (dd, J=8.0, 1.4, 1H), 7.83-7.76(dd, J=8.8, 1.7, 1H), 7.77-7.68 (m, 1H), 7.66-7.58 (m, 1H), 7.58-7.48(m, 2H), 7.46-7.39 (m, 2H), 7.37-7.30 (dd, J=7.4, 1.5, 1H), 4.31 (s,1H), 1.09 (s, 9H).

Example 428

N-tert-Butyl-4′-(5,6-diaminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromopyrazine-2,3-diamine. MS (ESI): mass calcd. forC₂₀H₂₂FN₅O₂S, 415.15; m/z found, 416.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.16-8.11 (dd, J=8.0, 1.3, 1H), 8.11-8.06 (m, 1H), 7.66 (s, 1H),7.66-7.62 (m, 1H), 7.60-7.54 (m, 1H), 7.40-7.35 (dd, J=7.5, 1.4, 1H),7.35-7.34 (m, 1H), 7.34-7.31 (dd, J=7.7, 1.6, 1H), 1.07 (s, 9H).

Example 429

N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-1H-imidazo[4,5-b]pyrazin-2(3H)-one. MS (ESI):mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 442.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.45-8.39 (d, J=1.7, 1H), 8.17-8.10 (m, 1H),8.06-7.98 (m, 1H), 7.70-7.60 (m, 1H), 7.60-7.52 (m, 1H), 7.42-7.38 (dd,J=7.4, 1.3, 1H), 7.38-7.33 (m, 2H), 1.07 (s, 9H).

Example 430

4′-(6-Amino-5-fluoropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-3-fluoropyridin-2-amine. MS (ESI): mass calcd.for C₂₁H₂₁F₂N₃O₂S, 417.13; m/z found, 418.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.16-8.11 (dd, J=8.0, 1.3, 1H), 8.04-7.97 (m, 2H), 7.69-7.62(m, 1H), 7.61-7.53 (m, 2H), 7.39-7.32 (m, 3H), 1.24-0.86 (s, 9H).

Example 431

N-tert-Butyl-4′-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine. MS(ESI): mass calcd. for C₂₃H₂₄FN₃O₂S, 425.16; m/z found, 426.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.18-8.06 (dd, J=7.9, 1.3, 1H), 7.95-7.85 (m,1H), 7.76 (s, 1H), 7.68-7.62 (m, 1H), 7.61-7.49 (m, 2H), 7.43-7.30 (m,3H), 4.03-3.92 (dd, J=8.8, 7.8, 2H), 3.37-3.32 (m, 2H), 1.10 (s, 9H).

Example 432

N-tert-Butyl-3′-fluoro-4′-(3H-imidazo[4,5-b]pyridin-6-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 6-bromo-3H-imidazo[4,5-b]pyridine. MS (ESI): masscalcd. for C₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.92 (s, 1H), 8.84-8.74 (m, 1H), 8.40 (s, 1H), 8.21-8.08(dd, J=8.1, 1.3, 1H), 7.70-7.63 (m, 2H), 7.62-7.55 (m, 1H), 7.46-7.36(m, 3H), 1.10 (s, 9H).

Example 433

4′-(5-Amino-6-methoxypyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-3-methoxypyrazin-2-amine. MS (ESI): masscalcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.18-8.10 (m, 2H), 7.95 (s, 1H), 7.68-7.62 (m, 1H),7.60-7.54 (m, 1H), 7.40-7.35 (m, 2H), 7.35-7.32 (dd, J=12.9, 1.6, 1H),4.19 (s, 3H), 1.07 (s, 9H).

Example 434

4′-(5-Amino-6-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 3-amino-6-bromopyrazine-2-carbonitrile. MS (ESI): masscalcd. for C₂₁H₂₀FN₅O₂S, 425.13; m/z found, 426.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.76-8.69 (d, J=2.1, 1H), 8.18-8.10 (dd, J=8.0, 1.3, 1H),7.96-7.89 (m, 1H), 7.68-7.62 (m, 1H), 7.61-7.53 (m, 1H), 7.40-7.37 (dd,J=7.6, 1.4, 1H), 7.37-7.36 (m, 1H), 7.36-7.33 (dd, J=4.4, 1.6, 1H), 1.07(s, 9H).

Example 435

4′-(5-Amino-3-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing6-amino-3-(4-bromo-2-fluorophenyl)pyrazine-2-carbonitrile and(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd.for O₂₁H₂₀FN₅O₂S, 425.13; m/z found, 426.1 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃) δ 8.25 (s, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 7.64-7.56 (m, 2H),7.54-7.49 (m, 1H), 7.47 (dd, J=7.9, 1.7, 1H), 7.40-7.33 (m, 2H), 1.04(s, 9H).

Example 436

4′-(6-Amino-4-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-amino-5-(4-bromo-2-fluorophenyl)pyridine-4-carbonitrile and(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃) δ 8.18 (d, J=7.8, 1H), 8.01 (s, 1H), 7.64-7.58 (m, 1H), 7.57-7.51(m, 1H), 7.46-7.28 (m, 4H), 3.91 (s, 1H), 1.04 (s, 9H).

Example 437

4′-(6-Amino-2-cyanopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂S, 424.14; m/z found, 424.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.11-8.04 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H),7.54-7.48 (m, 1H), 7.45-7.36 (dd, J=19.2, 9.2, 2H), 7.36-7.30 (dd,J=7.9, 1.6, 1H), 6.89-6.83 (d, J=8.7, 1H), 6.83-6.75 (d, J=10.0, 3H),1.03 (s, 9H).

Example 438

4′-(5-Amino-1,3,4-thiadiazol-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amineand 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. forC₁₈H₁₉FN₄O₂S₂, 406.09; m/z found, 407.1 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD)δ 8.20-8.10 (m, 2H), 7.69-7.56 (m, 2H), 7.46-7.36 (m, 3H), 1.08 (s, 9H).

Example 439

(R)-4′-(5-Amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amineand (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI):mass calcd. for C₁₇H₁₇FN₄O₃S₂, 408.07; m/z found, 409.1 [M+H]⁺. ¹H NMR(300 MHz, CD₃OD) δ 8.15-8.12 (m, 2H), 7.68 (m, 1H), 7.61 (m, 1H),7.44-7.38 (m, 3H), 3.42-3.38 (m, 1H), 3.30-3.25 (m, 1H), 3.22-3.18 (m,1H), 1.02 (d, J=6.6, 3H).

Example 440

4-((4′-(5-Amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine1,1-dioxide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amineand 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI):mass calcd. for C₁₈H₁₇FN₄O₄S₂, 468.04; m/z found, 469.0 [M+H]⁺. ¹H NMR(300 MHz, CD₃OD) δ 8.19 (m, 1H), 8.15 (dd, J=8.0, 1.1, 1H), 7.76 (m,1H), 7.67 (m, 1H), 7.45 (dd, J=7.6, 1.2, 1H), 7.39 (dd, J=11.9, 1.4,1H), 7.36 (dd, J=8.1, 1.6, 1H), 3.42-3.33 (m, 4H), 3.09-3.02 (m, 4H).

Example 441

4′-(5-Amino-6-chloropyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

To a 25 mL round-bottomed flask were added a stirbar, 52 mg (0.13 mmol)4′-(5-aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,27 mg (0.20 mmol) N-chlorosuccinamide, and dry DMF (2.0 mL). The flaskwas sparged with nitrogen and heated at 60° Celsius for 18 hours beforecooling to rt and subjecting the reaction mixture (after syringefiltration) to HPLC purification to give the title compound (29.6 mg,52%). MS (ESI): mass calcd. for C₂₀H₂₀ClFN₄O₂S, 434.10; m/z found, 435.1[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.44 (d, J=2.0, 1H), 8.06 (dd,J=8.1, 1.5, 1H), 7.85 (dd, J=9.4, 6.8, 1H), 7.70-7.64 (m, 1H), 7.64-7.57(m, 1H), 7.43-7.27 (m, 3H), 7.13 (s, 2H), 6.98 (d, J=3.7, 1H), 1.02 (s,9H).

Example 442

4′-(5-Amino-6-bromopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

To a 25 mL round-bottomed flask were added a stirbar, (55 mg, 14 mmol)4′-(5-aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide(32 mg, 0.18 mmol) NBS, and dry DMF (2.0 mL). The flask was sparged withnitrogen and stirred at rt for 18 hours before subjecting the reactionmixture (after syringe filtration) to HPLC purification to give thetitle compound (46 mg, 70%). MS (ESI): mass calcd. for C₂₀H₂₀BrFN₄O₂S,479.05; m/z found, 479.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.45 (d,J=1.8, 1H), 8.06 (dd, J=7.9, 1.4, 1H), 7.88-7.81 (m, 1H), 7.69-7.64 (m,1H), 7.64-7.58 (m, 1H), 7.37 (dd, J=7.6, 1.4, 1H), 7.35-7.29 (m, 2H),7.05 (s, 2H), 6.98 (s, 1H), 1.02 (s, 9H).

Example 443

6-Amino-3-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)picolinonitrile

The title compound was prepared using analogous conditions to thosedescribed in Example 62-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. forC₂₁H₁₆FN₃O₂S, 393.09; m/z found, 393.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.07 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48(m, 1H), 7.40 (dd, J=19.2, 9.2, 2H), 7.33 (dd, J=7.9, 1.6, 1H), 6.86 (d,J=8.7, 1H), 6.79 (d, J=10.0, 3H), 1.03 (s, 9H).

Example 444

N-tert-Butyl-3′-fluoro-4′-[1,2,4]triazolo[4,3-a]pyridin-7-ylbiphenyl-2-sulfonamide

To a 20 mL vial were addedN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide(45 mg, 0.10 mmol), 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (21 mg, 0.10mmol) K₂CO₃ (29 mg, 0.21 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (4 mg, 0.005 mmol),and a stir bar. The vial was sealed with a teflon lined cap and the vialsparged with N₂. The vial was then charged with freshly sparged DMSO (2mL) and stirred for 16 hours at 80° Celsius. The reaction mixture wasthen cooled to rt, filtered, and purified by HPLC to give the titlecompound (30 mg, 53%). MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂S, 424.14;m/z found, 425.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.40 (s, 1H), 8.79(s, 1H), 8.20-8.11 (m, 2H), 7.77 (m, 1H), 7.70-7.57 (m, 3H), 7.47-7.38(m, 3H), 1.10 (s, 9H).

Example 445

4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-3-methylpyrazin-2-amine. MS (ESI): mass calcd.for C₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.31-8.24 (m, 1H), 8.17-8.12 (dd, J=8.2, 1.3, 1H), 7.97-7.91(m, 1H), 7.68-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.43-7.36 (dd, J=7.5,1.3, 1H), 7.36-7.28 (m, 2H), 2.59-2.35 (m, 3H), 1.06 (s, 9H).

Example 446

4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared by forming4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidethen removing the tert-butyl group by dissolving the crude4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidein 1 mL of trifluoroacetic acid and heating it to 60° Celsius for 2hours, after which time the reaction was cooled to rt, concentrated todryness and purified using FCC. MS (ESI): mass calcd. for C₁₇H₁₅FN₄O₂S,358.09; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.22 (s, 1H),8.16-8.10 (dd, J=7.7, 1.3, 1H), 8.03-7.97 (m, 1H), 7.68-7.62 (m, 1H),7.61-7.54 (m, 1H), 7.41-7.37 (dd, J=7.7, 1.4, 1H), 7.36-7.33 (dd, J=8.0,1.7, 1H), 7.33-7.29 (dd, J=12.3, 1.6, 1H), 2.66-2.43 (m, 3H).

Example 447

N-tert-Butyl-3′-fluoro-4′-(1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-1H-imidazo[4,5-b]pyrazine. MS (ESI): masscalcd. for C₂₁H₂₀FN₅O₂S, 425.13; m/z found, 426.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 9.06-8.88 (d, J=2.1, 1H), 8.80 (s, 1H), 8.18-8.11 (dd,J=8.1, 1.3, 1H), 8.13-8.04 (m, 1H), 7.71-7.64 (m, 1H), 7.63-7.54 (m,1H), 7.48-7.39 (m, 3H), 1.09 (s, 9H).

Example 448

N-tert-Butyl-4′-(5,6-diaminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromopyridine-2,3-diamine. MS (ESI): mass calcd. forC₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.18-8.06 (m, 1H), 7.69-7.62 (m, 1H), 7.61-7.56 (m, 1H), 7.56-7.50 (m,2H), 7.47-7.42 (m, 1H), 7.40-7.30 (m, 3H), 1.104 (s, 9H).

Example 449

4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-3-methylpyrazin-2-amine and3′-fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide.MS (ESI): mass calcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.27 (s, 1H), 8.09-8.00 (d, J=7.9, 1H),7.96-7.87 (m, 1H), 7.71-7.63 (m, 1H), 7.63-7.55 (m, 1H), 7.44-7.38 (d,J=7.5, 1H), 7.34-7.21 (m, 2H), 2.46 (s, 3H), 2.44 (s, 3H).

Example 450

4′-(6-Amino-5-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 2-amino-5-bromonicotinonitrile. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ8.49-8.44 (m, 1H), 8.12 (d, J=1.8, 1H), 8.06 (dd, J=7.9, 1.3, 1H), 7.66(m, 1H), 7.63-7.56 (m, 2H), 7.38 (dd, J=7.5, 1.3, 1H), 7.33 (dd, J=11.9,1.6, 1H), 7.27 (dd, J=7.9, 1.7, 1H), 7.18 (s, 2H), 6.90 (s, 1H), 1.03(s, 9H).

Example 451

4′-(6-Amino-5-chloropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 5-bromo-3-chloropyridin-2-amine. MS (ESI): mass calcd. forC₂₁H₂₁ClFN₃O₂S, 433.10; m/z found, 434.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.20 (s, 1H), 8.06 (dd, J=7.9, 1.2, 1H), 7.85 (s, 1H), 7.66(m, 1H), 7.62-7.54 (m, 2H), 7.37 (m, 1H), 7.31 (dd, J=11.9, 1.6, 1H),7.26 (dd, J=7.9, 1.7, 1H), 6.89 (s, 1H), 6.62 (s, 2H), 1.03 (s, 9H).

Example 452

4′-[6-Amino-5-(trifluoromethyl)pyridin-3-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 5-bromo-3-(trifluoromethyl)pyridin-2-amine. MS (ESI): mass calcd.for C₂₂H₂₁F₄N₃O₂S, 467.13; m/z found, 468.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.47 (s, 1H), 8.07 (dd, J=7.9, 1.2, 1H), 7.96 (s, 1H), 7.66(m, 1H), 7.63-7.55 (m, 2H), 7.38 (dd, J=7.5, 1.3, 1H), 7.33 (dd, J=11.9,1.6, 1H), 7.27 (dd, J=7.9, 1.7, 1H), 6.88 (s, 1H), 6.76 (s, 2H), 1.02(s, 9H).

Example 453

4′-[2-Amino-4-(trifluoromethyl)pyrimidin-5-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine. MS (ESI): mass calcd.for C₂₁H₂₀F₄N₄O₂S, 468.12; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.45 (s, 1H), 8.07 (dd, J=7.8, 1.4, 1H), 7.67 (m, 1H), 7.62(m, 1H), 7.53 (s, 2H), 7.45-7.38 (m, 2H), 7.37-7.29 (m, 2H), 6.74 (s,1H), 1.01 (s, 9H).

Example 454

4-′-(2-Amino-4-methylpyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 usingN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamideand 5-bromo-4-methylpyrimidin-2-amine. MS (ESI): mass calcd. forC₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.17 (s, 1H), 8.08 (dd, J=8.0, 1.2, 1H), 7.67 (m, 1H), 7.64-7.58 (m,1H), 7.43-7.38 (m, 2H), 7.36 (dd, J=10.9, 1.6, 1H), 7.30 (dd, J=7.8,1.7, 1H), 7.13 (s, 2H), 6.86 (s, 1H), 2.25 (d, J=0.8, 3H), 1.00 (s, 9H).

3′-fluoro-4′-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamideStep A: 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde

Hexamethylenetetramine (1.08 g, 7.61 mmol) was added to a solution of5-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5 mol) in HOAc (6.34 mL). Themixture was heated at 100° Celsius for 6 hours. The reaction mixture wasthen cooled to rt and diluted with water. The mixture was extracted withEtOAc, dried (Na₂SO₄), filtered and concentrated to dryness. The residuewas purified by FCC to provide the title compound (379 mg, 33%). ¹H NMR(500 MHz, CDCl₃) δ 10.02 (s, 1H), 8.77 (d, J=2.2, 1H), 8.48 (d, J=2.2,1H), 7.99 (d, J=2.7, 1H).

Step B

The title compound was prepared using analogous conditions to thosedescribed in Example 88 using5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde and3′-fluoro-N-methyl-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide.MS (ESI): mass calcd. for C₂₁H₁₆FN₃O₃S, 409.09; m/z found, 410.2 [M+H]⁺.

N-(tert-butyl)-3′-fluoro-4′-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 88 using5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde andN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide.MS (ESI): mass calcd. for C₂₄H₂₂FN₃O₃S, 451.14; m/z found, 452.2 [M+H]⁺.

N-(tert-butyl)-3′-fluoro-4′-(7-nitro-1H-indol-5-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 88 using 5-bromo-7-nitroindole andN-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide.¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.27-8.18 (m, 2H), 7.65-7.58 (m,2H), 7.58-7.50 (m, 1H), 7.50-7.35 (m, 4H), 6.83-6.77 (m, 1H), 1.17-1.03(m, 9H).

Example 455

N-tert-Butyl-3′-fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]biphenyl-2-sulfonamide

The title compound was prepared using similar methods to those describedin Example 457 usingN-(tert-butyl)-3′-fluoro-4′-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-[1,1′-biphenyl]-2-sulfonamide.MS (ESI): mass calcd. for C₂₄H₂₄FN₃O₃S, 453.15; m/z found, 454.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.50 (s, 1H), 8.26-8.20 (m, 2H), 7.63-7.58 (m,1H), 7.56-7.48 (m, 3H), 7.44-7.39 (m, 1H), 7.39-7.34 (m, 3H), 4.92 (s,2H), 1.11 (d, J=12.1, 9H).

Example 456

4′-(7-Amino-1H-indol-5-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indol-7-amineand 2-bromo-N-(1-(hydroxymethyl)-cyclopentyl)benzene-sulfonamide in StepB. MS (ESI): mass calcd. for C₂₆H₂₆FN₃O₃S, 479.17; m/z found, 480.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (dd, J=8.1, 1.4, 1H), 8.13 (s,1H), 7.65-7.50 (m, 3H), 7.42 (s, 1H), 7.41-7.31 (m, 3H), 6.87 (m, 1H),6.61 (dd, J=3.1, 2.0, 1H), 4.05 (s, 1H), 3.48 (s, 2H), 1.50-1.34 (m,4H), 1.37-1.22 (m, 2H), 0.93-0.73 (m, 2H).

Example 457

3′-Fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methylbiphenyl-2-sulfonamide

NaBH₄ (4.45 mg, 0.13 mmol) was added to3′-fluoro-4′-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide(18 mg, 0.044 mmol) in MeOH (0.52 mL). The mixture was stirred at rt for1 h and then concentrated to dryness. The residue was subjected to FCCpurification to give the title compound. MS (ESI): mass calcd. forC₂₁H₁₈FN₃O₃S, 411.11; m/z found, 412.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ9.36 (s, 1H), 8.34 (s, 1H), 8.23 (dd, J=7.9, 1.2, 1H), 8.12 (s, 1H),7.68-7.61 (m, 1H), 7.61-7.54 (m, 1H), 7.42-7.30 (m, 5H), 5.21 (s, 1H),4.88 (s, 2H), 2.52 (dd, J=13.9, 5.3, 3H).

Example 458

4′-(7-Amino-1H-indol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

Zn dust (123 mg, 1.88 mmol) was added to a solution ofN-(tert-butyl)-3′-fluoro-4′-(7-nitro-1H-indol-5-yl)-[1,1′-biphenyl]-2-sulfonamide(23 mg, 0.19 mmol) and NH₄Cl (101 mg, 1.88 mmol) in water (0.75 mL) andacetone (3.76 mL). The mixture was stirred at rt for 1 hour and thenfiltered through Celite. The resulting filtrate was concentrated todryness and then taken up in water and extracted with EtOAc. The organicextract was dried (Na₂SO₄), filtered and concentrated to dryness to givethe title compound (23 mg, 28%). MS (ESI): mass calcd. for C₂₄H₂₄FN₃O₂S,437.16; m/z found, 438.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd,J=8.0, 1.3, 1H), 8.17-8.10 (m, 1H), 7.63-7.56 (m, 2H), 7.54-7.48 (m,1H), 7.42 (s, 1H), 7.38 (dd, J=7.8, 1.7, 2H), 7.32 (dd, J=11.4, 1.8,1H), 6.86 (m, 1H), 6.62 (dd, J=3.2, 2.0, 1H), 3.78-3.68 (m, 2H), 1.05(s, 9H).

Example 459

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]acetamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand N-(2-bromophenyl)acetamide. MS (ESI): mass calcd. for C₁₈H₁₅FN₄O,322.12; m/z found, 322.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s,1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.91 (m, 1H), 7.53-7.21 (m, 6H), 6.73(s, 2H), 1.92 (s, 3H).

Example 460

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]_(u) rea

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)urea. MS (ESI): mass calcd. for C₁₇H₁₄FN₅O, 323.12;m/z found, 323.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.02(s, 1H), 7.95 (m, 1H), 7.86 (d, J=8.9, 1H), 7.56 (s, 1H), 7.36-7.19 (m,4H), 7.08 (m, 1H), 6.73 (s, 2H), 6.01 (s, 2H).

5-(4-Bromo-2,3-difluorophenyl)pyrazin-2-amine

A mixture of (4-bromo-2,3-difluorophenyl)boronic acid (400 mg, 1.69mmol) and 5-bromopyrazin-2-amine (588 mg, 3.38 mmol was suspended inEtOH (5.6 ml) and toluene (5.7 mL) The resulting mixture was treatedwith aqueous Na₂CO₃ (2.0 N, 4.2 mL, 8.45 mmol). The resulting mixturewas then sparged with nitrogen through the mixture for 10 min, and thenPd(PPh₃)₄ (98 mg, 0.085 mmol) was added. The reaction vessel was sealedand heated at 80° Celsius for 17 hours. The reaction mixture was cooledto rt and then partitioned between saturated aqueous NH₄Cl and EtOAc.The organic layer was dried over MgSO₄ and concentrated to dryness. Theresidue was suspended in DCM and the solid isolated by filtration toafford the title compound (160 mg, 33%), which was used without furtherpurification. MS (ESI): mass calcd. for C₁₀H₆BrF₂N₃, 284.97; m/z found,286.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.01 (d, J=1.2,1H), 7.68-7.56 (m, 2H), 6.87 (s, 2H).

Example 461

5-[2,3-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

Nitrogen sparged DMSO (0.73 ml) was added to a mixture of5-(4-bromo-2,3-difluorophenyl)pyrazin-2-amine (50 mg, 0.18 mmol),(2-(methylsulfonyl)phenyl)boronic acid (35 mg, 0.18 mmol), K₂CO₃ (73 mg,0.532 mmol) and PdCl₂(dppf).CH₂Cl₂ (13 mg, 0.018 mmol) and heated at 80°Celsius for 2.5 hours. The mixture was cooled to rt and partitionedbetween sat. NaHCO₃ and EtOAc. The organic layer was isolated, driedover MgSO₄, and concentrated to dryness. Purification by FCC affordedthe title compound (26 mg, 41%). MS (ESI): mass calcd. forC₁₇H₁₃F₂N₃O₂S, 361.07; m/z found, 362.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.44-8.41 (m, 1H), 8.14 (dd, J=7.9, 1.4, 1H), 8.04 (d, J=1.5,1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.75-7.66 (m, 1H), 7.53 (dd, J=7.5,1.3, 1H), 7.30 (dd, J=11.6, 4.9, 1H), 6.85 (s, 2H), 3.06 (s, 3H).

Example 462

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide

The title compound was prepared by methods analogous to Example 461using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): masscalcd. for C₂₀H₂₀F₂N₄O₂S, 418.13; m/z found, 419.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.36 (s, 1H), 8.25 (dd, J=7.9, 1.3, 1H), 7.94 (d, J=1.4,1H), 7.71-7.66 (m, 1H), 7.60 (m, 1H), 7.55 (m, 1H), 7.34 (dd, J=7.4,1.1, 1H), 7.33-7.28 (m, 1H), 5.47 (s, 1H), 5.19 (s, 2H), 1.20 (s, 9H).

Example 463

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methylbiphenyl-2-yl]methanesulfonamideStep A: 5-(4-chloro-2-fluoro-3-methylphenyl)pyrazin-2-amine

The title compound was prepared by methods analogous to Intermediate HFusing (4-chloro-2-fluoro-3-methylphenyl)boronic acid. MS (ESI): masscalcd. for C₁₁H₉ClFN₃, 237.05; m/z found, 238.0 [M+H]⁺.

Step B

To a mixture of 5-(4-chloro-2-fluoro-3-methylphenyl)pyrazin-2-amine (75mg, 0.32 mmol), (2-(methylsulfonamido)phenyl)boronic acid (85 mg, 0.39mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(5.0 mg, 0.006 mmol) in a sealed tube flushed with N₂ were added N₂sparged K₃PO₄ (1.26 ml, 0.5 N) followed by N₂ sparged THF (0.63 ml). Thereaction mixture was stirred at rt for 18 hours. The reaction mixturewas then partitioned between EtOAc and brine. The organic layer wasisolated, dried over MgSO₄, filtered and concentrated to dryness.Purification by FCC afforded the title compound (100 mg, 85%). MS (ESI):mass calcd. for C₁₈H₁₇FN₄O₂S, 372.10; m/z found, 373.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.39-8.35 (m, 1H), 8.02 (d, J=1.5,1H), 7.70 (m, 1H), 7.47 (dd, J=8.1, 1.0, 1H), 7.45-7.39 (m, 1H), 7.29(m, 1H), 7.21 (dd, J=7.6, 1.5, 1H), 7.07 (d, J=8.0, 1H), 6.67 (s, 2H),2.87 (s, 3H), 2.01 (d, J=2.5, 3H).

Example 464

4′-(5-Aminopyrazin-2-yl)-2′,3′-difluorobiphenyl-2-sulfonamide

A suspension of4′-(5-aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide(168 mg, 0.40 mmol) in TFA (3 mL) was heated at 50° Celsius for 3 hours.The reaction was then cooled to rt and carefully partitioned betweenNaHCO₃ and EtOAc. The organic layer was isolated, dried over MgSO₄, andconcentrated to dryness. Purification by FCC afforded the title compound(140 mg, 96%). MS (ESI): mass calcd. for C₁₆H₁₂F₂N₄O₂S, 362.06; m/zfound, 363.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.12-8.01(m, 2H), 7.72-7.61 (m, 3H), 7.45-7.36 (m, 3H), 7.19 (m, 1H), 6.81 (s,2H).

5-(4-Bromo-2,3-difluorophenyl)pyrimidin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine using(4-bromo-2,3-difluorophenyl)boronic acid and 5-bromopyrimidin-2-amine.MS (ESI): mass calcd. for C₁₀H₆BrF₂N₃, 284.97; m/z found, 286.0 [M+H]⁺.

Example 465

4′-(2-Aminopyrimidin-5-yl)-2′,3′-difluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(4-bromo-2,3-difluorophenyl)pyrimidin-2-amine and(2-(N-methylsulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₁₇H₁₄F₂N₄O₂S, 376.08; m/z found, 377.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.56 (s, 2H), 7.98 (dd, J=7.7, 1.6, 1H), 7.72 (m, 2H), 7.45(dd, J=7.3, 1.6, 1H), 7.41 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.12 (s,2H), 2.40 (d, J=4.9, 3H).

Example 466

4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt

The title compound was prepared using analogous conditions to thosedescribed in Example 1 using5-(4-bromo-2,3-difluorophenyl)pyrimidin-2-amine and(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₂₀H₂₀F₂N₄O₂S, 418.13; m/z found, 419.1 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD) δ 8.63 (d, J=0.9, 2H), 8.15 (dd, J=7.9, 1.2, 1H), 7.67 (m, 1H),7.63-7.58 (m, 1H), 7.38 (dd, J=7.5, 1.3, 1H), 7.35-7.29 (m, 1H),7.27-7.18 (m, 1H), 1.13 (s, 9H).

Example 467

5-[2′,3-Difluoro-4′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-fluoro-4-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. forC₁₇H₁₀F₅N₃O, 367.07; m/z found, 368.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.40 (s, 1H), 8.03-7.96 (m, 2H), 7.78 (m, 1H), 7.56-7.49 (m, 3H), 7.37(d, J=8.2, 1H), 6.75 (s, 2H).

Example 468

5-(2′,3-Difluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromofluorobenzene. MS (ESI): mass calcd. for C₁₆H₁₁F₂N₃, 283.09;m/z found, 284.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.63-8.54 (m, 1H),8.13 (d, J=1.4, 1H), 8.00 (m, 1H), 7.52-7.31 (m, 4H), 7.24-7.12 (m, 2H),4.72 (s, 2H).

Example 469

5-(2′-Chloro-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromochlorobenzene. MS (ESI): mass calcd. for C₁₆H₁₁ClFN₃, 299.06;m/z found, 300.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.60 (s, 1H), 8.12(s, 1H), 7.98 (m, 1H), 7.54-7.44 (m, 1H), 7.41-7.23 (m, 5H), 4.68 (s,2H).

Example 470

5-(3-Fluoro-2′-methylbiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromotoluene. MS (ESI): mass calcd. for C₁₇H₁₄FN₃, 279.12; m/zfound, 280.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.12 (s,1H), 7.95 (m, 1H), 7.28-7.12 (m, 6H), 4.66 (s, 2H), 2.32 (s, 3H).

Example 471

5-[2′,3-Difluoro-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-fluoro-4-(trifluoromethyl)bromobenzene. MS (ESI): mass calcd. forC₁₇H₁₀F₅N₃, 351.08; m/z found, 351.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.42 (s, 1H), 8.11-7.97 (m, 2H), 7.90-7.83 (m, 2H), 7.71 (d, J=8.1, 1H),7.61-7.54 (m, 2H), 6.78 (s, 2H).

Example 472

5-[3-Fluoro-2′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-trifluoromethylbromobenzene. MS (ESI): mass calcd. for C₁₇H₁₁F₄N₃,333.09; m/z found, 334.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H),8.09 (s, 1H), 7.91 (m, 1H), 7.81 (d, J=7.6, 1H), 7.69 (m, 1H), 7.59 (m,1H), 7.44 (d, J=7.8, 1H), 7.23 (d, J=8.7, 1H), 7.17 (d, J=11.8, 1H).

Example 473

5-(3-Fluoro-2′-methoxybiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-methoxybromobenzene. MS (ESI): mass calcd. for C₁₇H₁₄FN₃O, 295.11;m/z found, 296.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.08(s, 1H), 7.85 (m, 1H), 7.45-7.29 (m, 4H), 7.14-7.00 (m, 2H), 3.84 (s,3H).

Example 474

5-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-thiomethylbromobenzene. MS (ESI): mass calcd. for C₁₇H₁₄FN₃S,311.09; m/z found, 312.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s,1H), 8.02 (d, J=1.2, 1H), 7.90 (m, 1H), 7.44-7.32 (m, 2H), 7.30 (s, 1H),7.27-7.18 (m, 3H), 6.71 (s, 2H), 2.40 (s, 3H).

Example 475

5-[3-Fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. forC₁₇H₁₁F₄N₃O, 349.08; m/z found, 350.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.39 (s, 1H), 8.02 (s, 1H), 7.96 (m, 1H), 7.65-7.47 (m, 4H), 7.42 (d,J=5.1, 1H), 7.39 (s, 1H), 6.73 (s, 2H).

Example 476

4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-ol

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromophenol. MS (ESI): mass calcd. for C₁₆H₁₂FN₃O, 281.10; m/zfound, 282.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.36 (s,1H), 8.01 (d, J=1.4, 1H), 7.87 (m, 1H), 7.49 (dd, J=4.4, 1.3, 1H), 7.45(s, 1H), 7.34 (dd, J=7.4, 1.3, 1H), 7.19 (m, 1H), 6.95 (d, J=7.3, 1H),6.89 (m, 1H), 6.68 (s, 2H).

Example 477

5-[3-Fluoro-2′-(phenylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-bromo-2-(phenylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₂H₁₆FN₃O₂S, 405.09; m/z found, 406.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.35 (s, 1H), 8.29 (dd, J=6.7, 2.5, 1H), 8.03 (d, J=1.4, 1H),7.80-7.66 (m, 3H), 7.58 (m, 1H), 7.41-7.28 (m, 5H), 6.84 (dd, J=8.0,1.6, 1H), 6.78-6.66 (m, 3H).

Example 478

5-(2′,3,6′-Trifluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2,6-difluorobromobenzene. MS (ESI): mass calcd. for C₁₆H₁₀F₃N₃,301.08; m/z found, 302.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s,1H), 8.02 (s, 1H), 7.97 (m, 1H), 7.56-7.47 (m, 1H), 7.43 (d, J=12.5,1H), 7.37 (d, J=7.9, 1H), 7.25 (m, 2H), 6.76 (s, 2H).

Example 479

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]benzenesulfonamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand N-(2-bromophenyl)benzenesulfonamide. MS (ESI): mass calcd. forC₂₂H₁₇FN₄O₂S, 420.11; m/z found, 421.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.73 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.85-7.75 (m, 1H), 7.59-7.46(m, 5H), 7.29-7.10 (m, 6H), 6.71 (s, 2H).

Example 480

5-(2′-Ethyl-3-fluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-ethylbromobenzene. MS (ESI): mass calcd. for C₁₈H₁₆FN₃, 293.13;m/z found, 294.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.03(d, J=1.3, 1H), 7.92 (m, 1H), 7.36 (d, J=3.9, 2H), 7.32-7.19 (m, 4H),6.71 (s, 2H), 2.60 (q, J=7.5, 2H), 1.06 (t, J=7.5, 3H).

Example 481

{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid

Step A: Methyl2-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)oxy)acetate

To a solution consisting of4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ol Example 476 (50 mg, 0.18mmol) and DMF (1 mL) was added Cs₂CO₃ (116 mg, 0.36 mmol). The mixturewas stirred at rt for 30 min. Methyl 2-bromoacetate (30 mg, 0.19 mmol)was added and the resultant mixture stirred at rt for 1 hour and thenpoured into 15 mL of water. The precipitate was collected and washedwith water and air dried to give methyl2-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)oxy)acetate(50 mg, 72%). MS (ESI): mass calcd. for C₁₉H₁₆FN₃O₃, 353.12; m/z found,354.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.03 (s, 1H),7.93 (m, 1H), 7.57 (d, J=13.0, 1H), 7.54 (d, J=9.2, 1H), 7.50 (d, J=7.4,1H), 7.34 (m, 1H), 7.10-7.02 (m, 2H), 6.70 (s, 2H), 4.89 (s, 2H), 3.71(s, 3H).

Step B

To a solution of methyl2-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yloxy)acetate (50 mg,0.14 mmol) in THF (2 mL) were added LiOH.H₂O (63 mg, 1.5 mmol) and H₂O(2 mL). The mixture was stirred at rt for 14 hours. The THF was removedunder reduced pressure, and the residue diluted with 15 mL of water,washed with DCM (5 mL×2), and then acidified with 1 N HCl to pH=7. Theprecipitate was collected and washed with water and dried under highvacuum to give the title compound (40 mg, 95% yield). MS (ESI): masscalcd. for C₁₈H₁₄FN₃O₃, 339.10; m/z found, 340.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 13.02 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.88 (m, 1H),7.55 (d, J=13.0, 1H), 7.48 (d, J=9.2, 1H), 7.40 (d, J=7.4, 1H), 7.33 (m,1H), 7.08-7.00 (m, 2H), 6.69 (s, 2H), 4.76 (s, 2H).

Example 482

5-[3-Fluoro-2′-(1-methylethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-isopropylbromobenzene. MS (ESI): mass calcd. for C₁₉H₁₈FN₃,307.15; m/z found, 308.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s,1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.49-7.34 (m, 2H), 7.27-7.17 (m, 4H),6.71 (s, 2H), 3.06-2.97 (m, 1H), 1.14 (d, J=6.8, 6H).

Example 483

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanone

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-acetylphenyl)boronicacid. MS (ESI): mass calcd. for C₁₈H₁₄FN₃O, 307.11; m/z found, 307.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.03 (d, J=1.2, 1H),7.91 (m, 1H), 7.69 (d, J=7.5, 1H), 7.61 (m, 1H), 7.53 (d, J=7.5, 1H),7.48 (d, J=8.2, 1H), 7.26 (d, J=12.4, 1H), 7.19 (dd, J=8.0, 1.3, 1H),6.75 (s, 2H), 2.31 (s, 3H).

Example 484

5-[3-Fluoro-2′-(2,2,2-trifluoroethoxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing what5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-(2,2,2-trifluoroethoxy)bromobenzene. MS (ESI): mass calcd. forC₁₈H₁₃F₄N₃O, 363.10; m/z found, 363.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.56-7.34 (m, 4H), 7.25 (d,J=8.0, 1H), 7.16 (m, 1H), 6.71 (s, 2H), 4.82 (q, J=8.8, 2H).

Example 485

4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxylic acid

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromobenzoic acid. MS (ESI): mass calcd. for C₁₇H₁₂FN₃O₂, 309.09;m/z found, 310.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 8.36(s, 1H), 8.02 (s, 1H), 7.87 (m, 1H), 7.76 (d, J=7.5, 1H), 7.60 (m, 1H),7.50 (d, J=7.2, 1H), 7.44 (d, J=8.2, 1H), 7.25 (d, J=5.1, 1H), 7.22 (s,1H), 6.70 (s, 2H).

Example 486

4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromobenzamide. MS (ESI): mass calcd. for C₁₇H₁₃FN₄O, 308.11; m/zfound, 309.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.01 (s,1H), 7.86 (m, 1H), 7.75 (s, 1H), 7.55-7.26 (m, 7H), 6.70 (s, 2H).

Example 487

5-[3-Fluoro-2′-(1-methylethoxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 3 using (2-isopropoxyphenyl)boronic acid and5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₉H₁₈FN₃O, 323.14; m/z found, 324.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.63-8.57 (m, 1H), 8.12 (d, J=1.4, 1H), 7.97-7.87 (m, 1H),7.48-7.42 (m, 1.5H), 7.42-7.34 (m, 1.5H), 7.34-7.28 (m, 1H), 7.07-6.97(m, 2H), 4.65 (s, 2H), 4.59-4.44 (m, 1H), 1.29 (d, J=6.1, 6H).

Example 488

5-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using(2-(cyclopropylmethoxy)pyridin-3-yl)boronic and5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₉H₁₇FN₄O, 336.14; m/z found, 337.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.64-8.59 (m, 1H), 8.17-8.09 (m, 2H), 8.02-7.93 (m, 1H),7.72-7.66 (m, 1H), 7.54-7.48 (m, 2H), 7.01-6.95 (m, 1H), 4.67 (s, 2H),4.24 (d, J=7.0, 2H), 1.37-1.22 (m, 1H), 0.66-0.54 (m, 2H), 0.42-0.31 (m,2H).

Example 489

2-[3,4′-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 377 using2-[3,4′-difluoro-2′-(methylthio)-[1,1′-biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine.MS (ESI): mass calcd. for C₁₉H₁₃F₂N₃O₂S, 385.07; m/z found, 386.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.48 (s, 1H), 8.82 (s, 1H), 8.27 (d,J=8.0, 1H), 8.18-8.09 (m, 1H), 7.77-7.67 (m, 2H), 7.66-7.57 (m, 1H),7.48-7.36 (m, 2H), 6.89-6.83 (m, 1H), 2.76 (s, 3H).

Example 490

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonmide Step A:N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide

To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1 g, 5 mmol) in pyridine (20 mL) was added methanesulfonyl chloride(627 mg, 5.5 mmol) and the mixture stirred at rt for 24 hours. Thesolvent was then removed under reduced pressure, and the resultingresidue redissolved in DCM (200 mL), washed with 1 N HCl (1×100 mL) and20% NaHCO₃ (1×100 mL). The organic layer was then isolated, dried(Na₂SO₄) and concentrated to dryness. The crude product was purified bycrystallization from DCM/hexanes to give the title compound (700 mg,52%). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 7.82-7.77 (m, 1H), 7.59(d, J=8.2, 1H), 7.51-7.43 (m, 1H), 7.17-7.10 (m, 1H), 2.95 (s, 3H), 1.37(s, 12H).

Step B:—N-Methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methane-sulfonamide

To a round bottom flask under nitrogen were addedN-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide(250 mg, 0.84 mmol), K₂CO₃ (140 mg, 1.01 mmol) and acetone (5.0 mL).Iodomethane (0.06 mL, 1 mmol) was then added to the mixture dropwise andthe reaction stirred for 18 hours at rt. The reaction was then dilutedwith ethyl acetate (100 mL), washed with water (2×) and brine (1×),dried (Na₂SO₄) and concentrated to dryness. The crude product waspurified by FCC providing the title compound (230 mg, 88%). ¹H NMR (400MHz, CDCl₃) δ 7.82 (dd, J=7.3, 1.8, 1H), 7.51-7.43 (m, 1H), 7.40-7.29(m, 2H), 3.32 (s, 3H), 2.93 (s, 3H), 1.36 (s, 12H).

Step C

The title compound was prepared using methods analogous to thosedescribed in Example 369 usingN-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamideand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.61-8.58 (m, 1H), 8.12 (d, J=1.5, 1H), 7.47-7.39 (m, 5H),7.37-7.31 (m, 1H), 7.30-7.23 (m, 1H), 4.75 (s, 2H), 3.17 (s, 3H), 2.76(s, 3H).

Example 491

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]ethanesulfonamideStep A:N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step A of Example 490 using2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andethanesulfonyl chloride. ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H),7.82-7.74 (m, 1H), 7.64 (d, J=8.3, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m,1H), 3.12 (q, J=7.4, 2H), 1.37 (s, 12H), 1.32 (t, J=7.4, 3H).

Step B

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 490 usingN-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamideand 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): masscalcd. for C₂₀H₁₇FN₄O₂S, 396.11; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 9.16 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 2H),7.75-7.66 (m, 2H), 7.47-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.27-7.20 (m,1H), 6.87-6.79 (m, 1H), 6.59 (s, 1H), 3.11 (q, J=7.4, 2H), 1.33-1.18 (m,3H).

Example 492

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylmethanesulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 490 using2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): masscalcd. C₂₀H₁₇FN₄O₂S, 396.11; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.69 (d, J=2.6, 1H), 8.05-7.99 (m, 1H), 7.97 (d, J=3.6, 1H),7.67-7.61 (m, 1H), 7.57-7.48 (m, 3H), 7.46-7.39 (m, 2H), 6.72 (d, J=3.6,1H), 4.75 (s, 1H), 3.14 (s, 3H), 2.99 (s, 3H).

Example 493

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylethanesulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 490 using2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): masscalcd. C₂₁H₁₉FN₄O₂S, 410.12; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 11.04 (s, 1H), 8.77 (d, J=2.7, 1H), 8.13-8.05 (m, 1H),7.70-7.63 (m, 1H), 7.53-7.42 (m, 4H), 7.40-7.30 (m, 2H), 6.78-6.71 (m,1H), 3.17 (s, 3H), 2.99-2.88 (m, 2H), 1.27 (t, J=7.4, 3H).

Example 494

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylethanesulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 usingN-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamideand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.1 [M+H]⁺. ¹H NMR (400 MHz,CDC₃) δ 8.63-8.57 (m, 1H), 8.13-8.09 (d, J=1.5, 1H), 8.04-7.95 (m, 1H),7.72-7.62 (m, 0.75H), 7.59-7.51 (m, 0.25H), 7.50-7.39 (m, 3.75H),7.37-7.32 (m, 1H), 7.31-7.28 (m, 0.25H), 4.69 (s, 2H), 3.16 (s, 3H),2.89 (q, J=7.4, 2H), 1.25 (t, J=7.4, 3H).

Example 495

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-2-methylpropane-1-sulfonamideStep A:N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropane-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 490 using2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andisobutylsulfonyl chloride. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H),7.81-7.75 (m, 1H), 7.63-7.58 (m, 1H), 7.49-7.41 (m, 1H), 7.14-7.06 (m,1H), 2.96 (d, J=10.1, 2H), 2.39-2.19 (m, 1H), 1.37 (s, 12H), 1.11-0.99(m, 6H).

Step B

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 490 usingN-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isobutylsulfonamideand 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): masscalcd. C₂₂H₂₁FN₄O₂S, 424.14; m/z found, 425.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.09 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 1H), 7.73-7.65(m, 2H), 7.46-7.37 (m, 1H), 7.34-7.29 (m, 2H), 7.26-7.19 (m, 2H),6.87-6.79 (m, 1H), 6.59 (s, 1H), 2.97 (d, J=6.6, 2H), 2.31-2.13 (m, 1H),1.05 (d, J=6.7, 6H).

Example 496

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamideStep A:—N-Ethyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 490 using iodoethane. ¹H NMR (400 MHz,CDCl₃) δ 7.87-7.82 (m, 1H), 7.50-7.44 (m, 1H), 7.40-7.31 (m, 2H), 3.72(q, J=7.1, 2H), 2.93 (s, 3H), 1.35 (s, 12H), 1.21-1.10 (m, 3H).

Step B

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 369 by usingN-ethyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamideand 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine. MS (ESI): mass calcd.C₁₉H₁₉FN₄O₂S.C₂HF₃O₂, 386.12; m/z found, 387.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.44 (d, J=1.2, 1H), 8.33 (d, J=1.2, 1H), 8.14-8.04 (m, 1H),7.51-7.33 (m, 6H), 3.46 (s, 2H), 2.95 (s, 3H), 1.05 (t, J=7.2, 3H).

Example 497

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,2-dimethylpropane-1-sulfonamideStep A:—N-Methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanesulfonamide

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 490 usingN-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 7.83-7.78 (m, 1H), 7.49-7.43 (m, 1H),7.38-7.29 (m, 2H), 3.30 (s, 3H), 2.97-2.91 (m, 2H), 2.38-2.23 (m, 1H),1.36 (s, 12H), 1.12-1.04 (m, 6H).

Step B

The title compound was prepared using methods analogous to thosedescribed in Step B of Example 369 usingN-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanesulfonamideand 5-(4-bromo-2-fluoro-phenyl)pyrazin-2-amine yielding the titlecompound after purification by HPLC (32 mg, 41%). MS (ESI): mass calcd.C₂₁H₂₃FN₄O₂S, 414.15; m/z found, 415.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.59 (s, 1H), 8.11 (d, J=1.3, 1H), 8.04-7.94 (m, 1H), 7.47-7.37 (m, 4H),7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H), 4.69 (s, 2H), 3.13 (s, 3H), 2.70(d, J=6.6, 2H), 2.26-2.11 (m, 1H), 1.00 (d, J=6.7, 6H).

Example 498

5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. forC₂₄H₂₀FN₃O₂, 401.15; m/z found, 402.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.16 (s, 1H), 8.58-8.48 (m, 1H), 8.21-8.13 (m, 1H), 7.61-7.30 (m, 8H),6.63-6.57 (m, 1H), 3.78-3.56 (m, 3H), 3.48-3.33 (m, 2H), 3.14-3.00 (m,1H), 2.94-2.75 (m, 2H).

Example 499

5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. forC₂₁H₁₉FN₄O₂, 378.15; m/z found, 379.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.56 (d, J=1.4, 2H), 7.54-7.41 (m, 5H), 7.36 (dd, J=8.0, 1.8, 1H), 7.32(dd, J=11.5, 1.8, 1H), 5.20 (s, 2H), 3.74-3.58 (m, 3H), 3.49-3.30 (m,2H), 3.15-3.01 (m, 1H), 2.94-2.77 (m, 2H).

Example 500

2-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using methods analogous to thosedescribed in Example 369 using (2-bromophenyl)(morpholino)methanone. MS(ESI): mass calcd. for C₂₃H₁₉FN₄O₂, 402.15; m/z found, 403.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.82 (d, J=2.5, 1H), 8.19-8.09 (m,1H), 7.71-7.65 (m, 1H), 7.55-7.34 (m, 6H), 6.87-6.80 (m, 1H), 3.74-3.57(m, 3H), 3.51-3.30 (m, 2H), 3.15-3.01 (m, 1H), 2.97-2.77 (m, 2H).

Example 501

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N-(tert-butyl)benzamide. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O, 364.17; m/z found, 365.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.55-8.50 (m, 1H), 8.13 (d, J=1.4, 1H), 8.04-7.95 (m, 1H), 7.64-7.58 (m,1H), 7.51-7.44 (m, 1H), 7.43-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.29-7.22(m, 1H), 5.69 (s, 1H), 5.45 (s, 2H), 2.65-2.54 (m, 1H), 1.24 (m, 9H).

Example 502

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromo-N-(tert-butyl)-5-fluorobenzamide. MS (ESI): mass calcd. forC₂₁H₂₀F₂N₄O, 382.16; m/z found, 383.2 [M+H]⁺.

Example 503

4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Example 369 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-bromo-N,N-diethylbenzamide. MS (ESI): mass calcd. for C₂₁H₂₁FN₄O,364.17; m/z found, 365.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59-8.54 (m,1H), 8.11 (d, J=1.5, 1H), 8.00-7.90 (m, 1H), 7.50-7.36 (m, 5H),7.36-7.29 (m, 1H), 4.69 (s, 2H), 3.87-3.69 (m, 1H), 3.17-2.92 (m, 2H),2.85-2.66 (m, 1H), 0.99 (t, J=7.1, 3H), 0.81 (t, J=7.1, 3H).

Example 504

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamideStep A: Methyl4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylate

A mixture of methyl 2-bromobenzoate (155 mg, 0.72 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(250 mg, 0.79 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (31 mg, 0.036 mmol) and K₂CO₃ (2mL, 2 N) in 1,4-dioxane (10 mL) was stirred at 60° Celsius under N₂ for3 hours. The solvent was removed and the crude product was purified byFCC to afford the desired product (218 mg, 93%). MS (ESI): mass calcd.for C₁₈H₁₄FN₃O₂, 323.11; m/z found, 323.9 [M+H]⁺.

Step B:4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid

A solution of methyl4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylate (218mg, 0.67 mmol) in NaOH (8 mL, 2 N) and THF (8 mL) was stirred at 80°Celsius for 48 hours, and then concentrated to dryness. The residue wasacidified with 2 N HCl. The precipitate was collected by filtration andwashed with water several times, and dried in vacuo to afford thedesired product (220 mg, 106%). The crude product was used withoutfurther purification. MS (ESI): mass calcd. for C₁₇H₁₂FN₃O₂, 309.09; m/zfound, 309.9 [M+H]⁺.

Step C

To a solution of DIPEA (47 mg, 0.36 mmol) in DMF (2 mL) were added4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid(75 mg, 0.24 mmol), (S)-1,1,1-trifluoropropan-2-amine (30 mg, 0.27 mmol)and HATU (110 mg, 0.290 mmol).

The reaction mixture was stirred at rt overnight. The solvent wasremoved and the residue was purified by FCC to afford the title compound(41 mg, 41%). MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found,404.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=8.9, 1H), 8.44 (d,J=1.4, 2H), 7.58-7.50 (m, 2H), 7.49-7.40 (m, 3H), 7.26-7.19 (m, 2H),6.86 (s, 2H), 4.60 (dd, J=15.7, 7.8, 1H), 1.15 (d, J=7.0, 3H).

Example 505

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid. MS(ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.91 (d, J=8.9, 1H), 8.46-8.28 (m, 1H), 8.01(d, J=1.4, 1H), 7.90-7.80 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.41 (m, 3H),7.28-7.20 (m, 2H), 6.69 (s, 2H), 4.66-4.57 (m, 1H), 1.16 (d, J=7.0, 3H).

Example 506

5-[3-Fluoro-2′-(piperazin-1-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andpiperazine. MS (ESI): mass calcd. for C₂₁H₂₀FN₅O, 377.17; m/z found,378.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.64-8.56 (m, 1H), 8.11 (d,J=1.5, 1H), 8.04-7.93 (m, 1H), 7.53-7.40 (m, 4H), 7.37 (dd, J=8.1, 1.8,1H), 7.30 (dd, J=12.2, 1.7, 1H), 4.77 (s, 2H), 3.72 (d, J=25.1, 2H),3.14 (s, 1H), 2.92 (s, 2H), 2.65 (s, 2H), 2.05 (s, 1H).

Example 507

5-{2′-[(4-Acetylpiperazin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid forand 1-(piperazin-1-yl)ethanone. MS (ESI): mass calcd. for C₂₃H₂₂FN₅O₂,419.18; m/z found, 420.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.65-8.56 (m,1H), 8.11 (d, J=1.5, 1H), 8.02 (dd, J=10.4, 5.8, 1H), 7.55-7.41 (m, 4H),7.42-7.32 (m, 1H), 7.34-7.28 (m, 1H), 4.71 (s, 2H), 3.65 (s, 2H),3.51-2.93 (m, 4H), 2.79 (s, 2H), 1.99 (d, 3H).

Example 508

4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andcyclohexanamine. MS (ESI): mass calcd. for C₂₃H₂₃FN₄O, 390.19; m/zfound, 391.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.60-8.53 (m, 1H), 8.11(d, J=1.5, 1H), 8.03-7.93 (m, 1H), 7.74-7.62 (m, 1H), 7.54-7.37 (m, 3H),7.32 (dd, J=8.0, 1.7, 1H), 7.30-7.20 (m, 1H), 5.24 (d, J=8.3, 1H), 4.72(s, 2H), 3.93-3.73 (m, 1H), 1.78-1.67 (m, 2H), 1.61-1.44 (m, 3H),1.39-1.27 (m, 2H), 1.14-0.98 (m, 1H), 0.97-0.81 (m, 2H).

Example 509

5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andthiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₃S,426.12; m/z found, 427.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H),8.11 (s, 1H), 8.11-8.02 (m, 1H), 7.58-7.47 (m, 3H), 7.43 (d, J=7.5, 1H),7.37 (dd, J=8.1, 1.8, 1H), 7.32 (dd, J=12.1, 1.7, 1H), 4.74 (s, 2H),4.23 (s, 1H), 4.05 (s, 1H), 3.57-3.48 (m, 1H), 3.38 (s, 1H), 3.01 (s,1H), 2.85 (s, 1H), 2.62 (s, 1H), 2.05 (s, 1H).

Example 510

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andmethylamine. MS (ESI): mass calcd. for C₁₈H₁₅FN₄O, 322.12; m/z found,323.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (dd, J=2.3, 1.6, 1H),8.15 (d, J=4.7, 1H), 8.00 (d, J=1.5, 1H), 7.84 (d, J=8.1, 1H), 7.52-7.41(m, 4H), 7.27 (s, 1H), 7.24 (dd, J=5.5, 1.7, 1H), 6.68 (s, 2H), 2.59 (d,J=4.6, 3H).

Example 511

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and(R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.91 (d, J=8.8, 1H) 8.34 (s, 1H), 8.01 (d, J=1.2, 1H), 7.90-7.80 (m,1H), 7.58-7.40 (m, 4H), 7.29-7.18 (m, 2H), 6.69 (s, 2H), 4.68-4.56 (m,1H), 1.16 (d, J=7.0, 3H).

Example 512

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and(R)-2-aminopropan-1-ol. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₂, 366.15;m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H),8.15-7.97 (m, 2H), 7.94-7.82 (m, 1H), 7.55-7.39 (m, 4H), 7.37-7.26 (m,2H), 6.71 (s, 2H), 4.64 (s, 1H), 3.92-3.73 (m, 1H), 3.26-3.10 (m, 2H),0.98 (d, J=6.1, 3H).

Example 513

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and(S)-2-aminopropan-1-ol for (S)-1,1,1-trifluoropropan-2-amine. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 367.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.05 (d, J=5.1, 2H), 7.93-7.83 (m,1H), 7.54-7.43 (m, 3H), 7.37-7.28 (m, 2H), 6.72 (s, 2H), 4.66 (t, J=5.6,1H), 3.82 (d, J=7.0, 1H), 3.35 (s, 1H), 3.16 (d, J=10.4, 2H), 0.98 (d,J=6.6, 3H).

Example 514

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-4-ol

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andpiperidin-4-ol. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂, 392.16; m/zfound, 393.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due to the presenceof multiple conformations on the NMR time-scale, peaks listed foridentification purposes only: δ 8.54 (d, J=13.9), 8.11-8.05 (m),7.98-7.83 (m), 7.47-7.27 (m), 6.72 (s), 4.68 (s), 4.24-4.05 (m),3.76-3.53 (m), 3.27-3.18 (m), 2.91-2.80 (m), 2.62-2.51 (m), 1.82 (m),1.69 (m), 1.51-1.45 (m), 1.26-1.18 (m), 0.48-0.41 (m).

Example 515

5-{2′-[(4-Aminopiperidin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andpiperidin-4-amine. MS (ESI): mass calcd. for C₂₂H₂₂FN₅O, 391.18; m/zfound, 392.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.99 (s,1H), 7.88 (s, 1H), 7.48 (d, J=14.8, 3H), 7.35-7.20 (m, 3H), 6.69 (s,2H), 4.31 (s, 1H), 3.08-2.50 (m, 6H), 1.75 (t, J=80.9, 2H), 1.38-0.86(m, 2H).

Example 516

5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using thiomorpholine 1,1-dioxide. MS(ESI): mass calcd. for C₂₁H₁₉FN₄O₃S, 426.12; m/z found, 426.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.43 (s, 2H), 7.63 (s, 1H), 7.52 (d, J=20.5,4H), 7.30 (dd, J=16.9, 9.9, 2H), 6.89 (s, 2H), 3.97 (s, 1H), 3.84 (s,1H), 3.46 (s, 1H), 3.32 (s, 1H), 3.02 (s, 1H), 2.85 (s, 1H), 2.47 (s,1H), 2.11 (s, 1H).

Example 517

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using (S)-2-aminopropan-1-ol. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 366.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.46 (s, 2H), 8.00 (d, J=8.1, 1H), 7.62-7.50(m, 1H), 7.48 (d, J=4.1, 1H), 7.43 (d, J=7.3, 3H), 7.34-7.23 (m, 2H),6.88 (s, 2H), 4.61 (s, 1H), 3.87-3.75 (m, 1H), 3.38 (s, 1H), 3.14 (s,1H), 0.96 (d, J=6.6, 3H).

Example 518

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using(R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₀H₁₆F₄N₄O, 404.13; m/z found, 404.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.52 (d, J=1.0, 2H), 7.68 (dd, J=7.6, 1.4, 1H), 7.60-7.49 (m, 1H),7.48-7.38 (m, 3H), 7.28-7.25 (m, 1H), 7.22 (dd, J=11.1, 1.7, 1H), 5.39(d, J=9.6, 1H), 5.18 (s, 2H), 4.73 (m, 1H), 1.12 (d, J=7.0, 3H).

Example 519

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid andpiperazin-2-one. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O₂, 391.14; m/zfound, 392.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due to the presenceof multiple conformations on the NMR time-scale, peaks listed foridentification purposes only: δ 8.58-8.55 (m), 8.50-8.40 (m), 8.10 (d,J=1.5), 8.04-7.98 (m), 7.56-7.41 (m), 7.37-7.27 (m), 6.75 (s), 6.43 (s),5.06 (s), 4.83 (s), 4.45 (d, J=19.2), 4.05-3.95 (m), 3.72-3.46 (m), 3.27(s), 3.14 (s), 2.97 (s), 2.67 (s).

Example 520

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one

The title compound was prepared using methods analogous to thosedescribed in Step C of Example 504 using piperazin-2-one. MS (ESI): masscalcd. for C₂₁H₁₈FN₅O₂, 391.14; m/z found, 391.9 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) Complex due to the presence of multiple conformations on theNMR time-scale, peaks listed for identification purposes only: δ 8.47(d, J=1.2), 8.41 (d, J=1.2), 7.49-7.34 (m), 7.29-7.19 (m), 6.68 (s),6.35 (s), 5.45 (s), 5.25 (s), 4.38 (d, J=18.7), 4.03 (s), 3.59-3.50 (m),3.31-2.88 (m), 2.64 (s).

(2-Bromo-5-(trifluoromethyl)phenyl)(morpholino)methanone

2-Bromo-5-(trifluoromethyl)benzoic acid (200 mg, 0.74 mmol) wasdissolved in DMF (4.65 mL) and HATU (424 mg, 1.12 mmol) added to theresultant mixture at rt. The solution was stirred for 10 min thentreated with N,N-diisopropylethylamine (0.51 mL, 3.0 mmol) andmorpholine (0.096 mL, 1.1 mmol). The reaction was stirred for 15 hoursthen quenched by the addition of saturated NH₄Cl (5 mL) and EtOAc (5mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) andthe combined organic extracts washed with brine, dried over Na₂SO₄ andconcentrated to dryness. The crude product was purified by FCC to givethe title compound. ¹H NMR (500 MHz, CDCl₃) δ 7.76-7.71 (m, 1H),7.55-7.49 (m, 2H), 3.92-3.86 (m, 1H), 3.83-3.69 (m, 4H), 3.66-3.58 (m,1H), 3.32-3.24 (m, 1H), 3.25-3.17 (m, 1H).

Example 521

5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(2-bromo-5-(trifluoromethyl)phenyl)(morpholino)-methanone. MS (ESI):mass calcd. for C₂₂H₁₈F₄N₄O₂, 446.14; m/z found, 447.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.40 (s, 1H), 8.18 (s, 1H), 8.10-8.01 (m, 1H),7.90-7.82 (d, J=7.9, 1H), 7.78-7.69 (m, 2H), 7.47-7.35 (m, 2H),3.72-3.60 (dd, J=10.0, 4.2, 2H), 3.58-3.49 (m, 1H), 3.44-3.36 (m, 1H),3.15-3.04 (m, 1H), 2.90-2.80 (dd, J=13.4, 5.2, 1H), 2.80-2.72 (m, 1H).

Example 522

5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(2-bromo-5-(trifluoromethyl)phenyl)(morpholino)methanone and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₈F₄N₄O₂, 446.14; m/z found, 447.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.65-8.58 (d, J=1.3, 2H), 7.91-7.85 (dd,J=8.3, 1.9, 1H), 7.78-7.76 (m, 1H), 7.76-7.73 (d, J=8.1, 1H), 7.71-7.63(m, 1H), 7.46-7.43 (dd, J=2.7, 1.8, 1H), 7.43-7.41 (dd, J=6.2, 1.7, 1H),3.72-3.60 (m, 2H), 3.60-3.52 (m, 1H), 3.46-3.39 (m, 1H), 3.37-3.33 (m,1H), 3.16-3.09 (m, 1H), 2.92-2.77 (m, 2H).

Example 523

4-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand 4-(2-bromophenoxy)pyrimidin-2-amine. MS (ESI): mass calcd. forC₂₃H₁₆FN₅O, 397.13; m/z found, 398.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.30 (s, 1H), 8.55-8.45 (m, 1H), 8.18-8.08 (m, 1H), 8.07 (d, J=5.7, 1H),7.55-7.28 (m, 8H), 7.22 (dd, J=8.0, 1.4, 1H), 6.08 (d, J=5.7, 1H), 4.95(s, 2H).

Example 524

2-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-4-amine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. forC₂₃H₁₆FN₅O, 397.13; m/z found, 398.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.94 (s, 1H), 8.47 (s, 1H), 8.11 (d, J=2.1, 1H), 7.96 (d, J=5.7, 1H),7.54-7.30 (m, 9H), 6.07 (d, J=5.7, 1H), 4.96-4.85 (m, 2H).

Example 525

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared using methods analogous to thosedescribed in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. for C₂₃H₁₅FN₄O,382.12; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1H),8.51-8.42 (m, 3H), 8.14-8.05 (m, 1H), 7.57-7.28 (m, 8H), 6.99-6.89 (m,1H), 6.55 (dd, J=3.6, 1.8, 1H).

2-(2-Bromophenoxy)pyrimidine

To a 48 mL pressure tube containing a stirbar were added2-chloropyrimidine (1.69 g, 14.7 mmol), 2-bromophenol (1.63 mL, 14.0mmol), Cs₂CO₃ (5.49 g, 16.8 mmol) and DMSO (30 mL). The vial was sealedand heated at 120° Celsius for 15 hours. The reaction was then dilutedwith 100 mL of ethyl acetate and extracted with brine (2×50 mL). Theorganic layer was isolated, dried and concentrated to dryness to providethe crude product which was subsequently purified FCC to provide thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (s, 1H), 8.56 (s, 1H),7.72-7.60 (dd, J=8.0, 1.6, 1H), 7.45-7.34 (m, 1H), 7.32-7.23 (m, 1H),7.23-7.11 (m, 1H), 7.10-7.01 (t, J=4.8, 1H).

2-(2-Bromophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloropyrimidin-4-amine. ¹H NMR (500 MHz,CDCl₃) δ 8.04-7.94 (d, J=5.7, 1H), 7.66-7.58 (dd, J=8.0, 1.5, 1H),7.41-7.30 (m, 1H), 7.30-7.20 (m, 1H), 7.18-7.05 (m, 1H), 6.20-6.09 (d,J=5.7, 1H), 5.19 (s, 2H).

4-(2-Bromophenoxy)pyrimidin-2-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloropyrimidin-2-amine. ¹H NMR (500 MHz,CDCl₃) δ 8.15-8.12 (d, J=5.6, 1H), 7.65-7.61 (dd, J=8.0, 1.6, 1H),7.37-7.32 (m, 1H), 7.20-7.16 (dd, J=8.1, 1.5, 1H), 7.16-7.09 (m, 1H),6.19-6.14 (d, J=5.7, 1H), 5.21 (s, 2H).

6-(2-Bromophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 6-chloropyrimidin-4-amine. ¹H NMR (500 MHz,DMSO-d₆) δ 7.95 (d, J=0.8, 1H), 7.67-7.62 (m, 1H), 7.38 (m, 1H),7.20-7.14 (m, 2H), 6.75 (s, 2H), 5.77 (d, J=0.9, 1H).

2-(2-Bromophenoxy)-4-methylpyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-4-methylpyrimidine. ¹H NMR (500 MHz,DMSO-d₆) δ 8.44 (d, J=5.1, 1H), 7.72 (dd, J=8.0, 1.6, 1H), 7.49-7.43 (m,1H), 7.34 (dd, J=8.0, 1.6, 1H), 7.26-7.20 (m, 1H), 7.17-7.14 (m, 1H),2.41 (s, 3H).

4-(2-Bromophenoxy)-2-methylpyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloro-2-methylpyrimidine. ¹H NMR (500 MHz,CDCl₃) δ 8.47 (d, J=5.8, 1H), 7.64 (dd, J=8.0, 1.5, 1H), 7.42-7.33 (m,1H), 7.23-7.10 (m, 2H), 6.64 (d, J=5.7, 1H), 2.55 (s, 3H).

2-(2-Bromophenoxy)nicotinonitrile

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloronicotinonitrile. ¹H NMR (500 MHz,CDCl₃) δ 8.32-8.21 (dd, J=5.0, 1.9, 1H), 8.09-7.95 (dd, J=7.6, 1.9, 1H),7.68-7.60 (dd, J=8.0, 1.5, 1H), 7.45-7.36 (m, 1H), 7.29-7.23 (dd, J=8.1,1.5, 1H), 7.21-7.16 (m, 1H), 7.15-7.09 (dd, J=7.6, 5.0, 1H).

4-(2-Bromophenoxy)picolinonitrile

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloropicolinonitrile. ¹H NMR (500 MHz,DMSO-d₆) δ 8.60-8.55 (m, 1H), 7.82-7.77 (m, 1H), 7.73-7.66 (m, 1H), 7.51(m, 1H), 7.42-7.36 (m, 1H), 7.34-7.27 (m, 1H), 7.11-7.06 (m, 1H).

2-(2-Bromophenoxy)-5-methoxypyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-5-methoxypyrimidine. ¹H NMR (500 MHz,DMSO-d₆) δ 8.41 (d, J=0.6, 2H), 7.73 (d, J=8.0, 1H), 7.46 (m, 1H), 7.33(d, J=8.1, 1H), 7.23 (m, 1H), 3.87 (d, J=0.5, 3H).

4-(2-Bromophenoxy)-2-(trifluoromethyl)pyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloro-2-(trifluoromethyl)pyrimidine. ¹H NMR(500 MHz, DMSO-d₆) δ 8.92 (d, J=5.8, 1H), 7.76 (dd, J=8.0, 1.5, 1H),7.53-7.40 (m, 3H), 7.29 (m, 1H).

4-(Azetidin-1-yl)-6-(2-bromophenoxy)pyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-(azetidin-1-yl)-6-chloropyrimidine. ¹H NMR(400 MHz, DMSO-d₆) δ 8.10 (d, J=0.8, 1H), 7.70 (dd, J=8.0, 1.5, 1H),7.43 (m, 1H), 7.30-7.18 (m, 2H), 5.84 (d, J=0.8, 1H), 4.06-3.97 (m, 4H),2.41-2.30 (m, 2H).

2-(2-Bromo-5-(trifluoromethyl)phenoxy)pyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-bromo-5-(trifluoromethyl)phenol. ¹H NMR (500MHz, CDC₃) δ 8.62-8.49 (d, J=4.8, 2H), 7.82-7.75 (dd, J=8.4, 0.9, 1H),7.54-7.51 (d, J=2.0, 1H), 7.44-7.40 (m, 1H), 7.13-7.08 (m, 1H).

6-((2-Bromophenoxy)methyl)picolinonitrile

To a sealable 4 mL vial, containing 6-(chloromethyl)picolinonitrile (100mg, 0.66 mmol) and 2-bromophenol (113 mg, 0.66 mmol), were added Cs₂CO₃(320 mg, 0.98 mmol) and acetonitrile (1.7 mL). The vial was then heatedat 80° Celsius for 15 hours. The reaction was then diluted with ethylacetate, filtered through a celite plug and concentrated to dryness. Thematerial was used without further purification. ¹H NMR (500 MHz, CDCl₃)δ 8.02-7.93 (m, 1H), 7.93-7.85 (m, 1H), 7.65-7.59 (dd, J=7.7, 1.1, 1H),7.58-7.53 (dd, J=7.9, 1.6, 1H), 7.29-7.22 (m, 1H), 6.93-6.90 (dd, J=8.3,1.3, 1H), 6.90-6.86 (m, 1H), 5.23 (s, 2H).

2-((2-Bromophenoxy)methyl)nicotinonitrile

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-(chloromethyl)nicotinonitrile. ¹H NMR (500MHz, CDCl₃) δ 8.83-8.74 (dd, J=4.9, 1.7, 1H), 8.02-7.97 (dd, J=7.9, 1.7,1H), 7.57-7.49 (dd, J=7.9, 1.6, 1H), 7.42-7.35 (dd, J=7.9, 4.9, 1H),7.27-7.20 (m, 1H), 7.08-7.01 (dd, J=8.2, 1.3, 1H), 6.91-6.83 (m, 1H),5.37 (s, 2H).

Example 526

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. forC₂₀H₁₄FN₅O, 359.12; m/z found, 360.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.56 (d, J=4.8, 2H), 8.35-8.30 (m, 1H), 7.99 (d, J=1.5, 1H), 7.82 (m,1H), 7.58 (dd, J=7.6, 1.7, 1H), 7.52-7.46 (m, 1H), 7.42-7.28 (m, 4H),7.17 (t, J=4.8, 1H), 6.70 (s, 2H).

Example 527

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₄FN₅O, 359.12; m/z found, 360.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (d, J=4.8, 2H), 8.43 (d, J=1.4, 2H),7.58-7.46 (m, 3H), 7.42-7.27 (m, 4H), 7.20 (t, J=4.8, 1H), 6.88 (s, 2H).

Example 528

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): masscalcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.35-8.28 (dd, J=2.1, 1.5, 1H), 8.08-8.00 (d, J=1.5, 1H),7.84-7.77 (m, 1H), 7.77-7.71 (d, J=5.9, 1H), 7.52-7.47 (dd, J=7.6, 1.7,1H), 7.46-7.40 (m, 1H), 7.38-7.32 (m, 2H), 7.32-7.27 (dd, J=12.6, 1.7,1H), 7.23-7.16 (dd, J=8.1, 1.2, 1H), 6.11-6.09 (d, J=5.9, 1H).

Example 529

5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.49-8.43 (d, J=1.4, 2H), 7.79-7.72 (d, J=5.9,1H), 7.51-7.47 (dd, J=7.6, 1.7, 1H), 7.47-7.41 (m, 2H), 7.39-7.28 (m,3H), 7.22-7.17 (dd, J=8.1, 1.2, 1H), 6.16-6.05 (d, J=105.9, 1H).

Example 530

6-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 6-((2-bromophenoxy)methyl)picolinonitrile. MS (ESI):mass calcd. for C₂₃H₁₆FN₅O, 397.13; m/z found, 398.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.38-8.29 (d, J=1.5, 1H), 8.24 (s, 1H), 8.01-7.90 (m, 2H),7.83-7.73 (m, 1H), 7.72-7.64 (dd, J=8.2, 1.0, 1H), 7.52-7.48 (dd, J=8.1,1.6, 1H), 7.48-7.44 (m, 1H), 7.44-7.40 (dd, J=7.6, 1.7, 1H), 7.40-7.34(m, 1H), 7.19-7.15 (dd, J=8.3, 1.1, 1H), 7.14-7.07 (m, 1H), 5.26 (s,2H).

Example 531

2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-3-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 2-((2-bromophenoxy)methyl)nicotinonitrile. MS (ESI):mass calcd. for C₂₃H₁₆FN₅O, 397.13; m/z found, 398.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.80-8.73 (dd, J=5.0, 1.7, 1H), 8.32-8.27 (m, 1H),8.24-8.22 (d, J=1.4, 1H), 8.22-8.15 (dd, J=7.9, 1.7, 1H), 7.89-7.82 (m,1H), 7.57-7.49 (dd, J=7.9, 5.0, 1H), 7.45 (s, 1H), 7.44-7.42 (dd, J=4.4,1.6, 1H), 7.41-7.35 (m, 2H), 7.26-7.22 (dd, J=8.2, 1.0, 1H), 7.14-7.09(m, 1H), 5.34 (s, 2H).

Example 532

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)nicotinonitrile. MS (ESI): masscalcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.28-8.25 (m, 1H), 8.22-8.18 (d, J=1.4, 1H), 8.17-8.13 (dd,J=5.0, 1.9, 1H), 8.10-8.04 (dd, J=7.6, 1.9, 1H), 7.89-7.82 (m, 1H),7.57-7.53 (dd, J=7.6, 1.7, 1H), 7.53-7.47 (m, 1H), 7.45-7.41 (m, 1H),7.41-7.37 (dd, J=8.1, 1.7, 1H), 7.34-7.28 (m, 2H), 7.12-7.04 (dd, J=7.6,5.0, 1H).

Example 533

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)pyrimidin-2-amine. MS (ESI): masscalcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.35-8.29 (m, 1H), 8.12-8.07 (d, J=1.5, 1H), 8.05-8.00 (d,J=7.0, 1H), 7.92-7.85 (m, 1H), 7.59-7.55 (dd, J=7.5, 1.8, 1H), 7.55-7.49(m, 1H), 7.49-7.43 (m, 1H), 7.36-7.33 (dd, J=8.1, 1.7, 1H), 7.33-7.31(dd, J=8.0, 1.3, 1H), 7.31-7.27 (dd, J=12.5, 1.7, 1H), 6.72-6.42 (d,J=7.0, 1H).

Example 534

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)pyrimidin-2-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.46 (s, 2H), 7.98-7.94 (d, J=5.8, 1H),7.53-7.49 (d, J=7.6, 1H), 7.49-7.42 (m, 2H), 7.41-7.36 (m, 1H),7.36-7.32 (d, J=8.2, 1H), 7.32-7.27 (m, 1H), 7.26-7.14 (d, J=8.0, 1H),6.13-6.04 (d, J=5.8, 1H).

Example 535

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): masscalcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.24 (s, 1H), 7.97 (d, J=1.4, 1H), 7.90 (s, 1H), 7.74 (m,1H), 7.50 (dd, J=7.6, 1.7, 1H), 7.42 (m, 1H), 7.36-7.29 (m, 2H),7.28-7.22 (m, 1H), 7.13 (d, J=8.1, 1H), 6.65 (s, 2H), 6.52 (s, 2H), 5.67(s, 1H).

Example 536

5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)pyrimidin-4-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s, 2H), 7.92 (s, 1H), 7.47 (m, 2H),7.40 (d, J=6.4, 1H), 7.36-7.23 (m, 3H), 7.11 (d, J=7.7, 1H), 6.68 (br,4H), 5.68 (s, 1H).

Example 537

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)picolinonitrile. MS (ESI): masscalcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.47 (d, J=5.1, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.81 (s,1H), 7.66-7.56 (m, 2H), 7.48 (dd, J=20.1, 7.3, 2H), 7.39-7.20 (m, 3H),7.07 (s, 1H), 6.68 (s, 2H).

Example 538

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)picolinonitrile and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (d, J=5.7, 1H), 8.40 (d, J=1.3, 2H),7.61 (dd, J=7.9, 2.0, 2H), 7.53 (dd, J=11.1, 5.0, 2H), 7.48-7.42 (m,1H), 7.36 (dd, J=12.1, 1.5, 1H), 7.31 (dd, J=11.5, 5.0, 2H), 7.11 (dd,J=5.7, 2.5, 1H), 6.86 (s, 2H).

Example 539

5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(azetidin-1-yl)-6-(2-bromophenoxy)pyrimidine. MS(ESI): mass calcd. for C₂₃H₁₉FN₆O, 414.16; m/z found, 415.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.39-8.31 (m, 1H), 8.08 (d, J=0.9, 1H), 8.02(d, J=1.5, 1H), 7.85 (m, 1H), 7.55 (dd, J=7.6, 1.7, 1H), 7.51-7.42 (m,1H), 7.40-7.29 (m, 3H), 7.18 (dd, J=8.0, 1.2, 1H), 6.71 (s, 2H), 5.71(d, J=0.9, 1H), 3.96 (t, J=7.5, 4H), 2.39-2.24 (m, 2H).

Example 540

5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(azetidin-1-yl)-6-(2-bromophenoxy)pyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₃H₁₉FN₆O, 414.16; m/z found, 415.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=1.5, 2H), 8.11 (d, J=0.9, 1H),7.60-7.52 (m, 2H), 7.50-7.41 (m, 1H), 7.41-7.31 (m, 3H), 7.17 (dd,J=8.1, 1.2, 1H), 6.89 (s, 2H), 5.73 (d, J=0.9, 1H), 3.98 (t, J=7.5, 4H),2.41-2.27 (m, 2H).

Example 541

5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-methylpyrimidine. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.53 (s, 1H), 8.35 (d, J=5.8, 1H), 8.08 (d, J=1.3, 1H), 7.87(m, 1H), 7.51 (dd, J=7.5, 1.9, 1H), 7.45 (m, 1H), 7.38 (dd, J=7.8, 6.9,1H), 7.33 (dd, J=7.9, 1.6, 1H), 7.26 (m, 1H), 7.21 (d, J=8.1, 1H), 6.49(d, J=5.8, 1H), 4.73 (s, 2H), 2.51 (s, 3H).

Example 542

5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]penyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-methylpyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.50 (s, 2H), 8.38 (d, J=5.8, 1H), 7.53-7.28(m, 6H), 7.21 (d, J=7.9, 1H), 6.51 (d, J=5.7, 1H), 5.30 (s, 2H), 2.52(s, 3H).

Example 543

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-benzimidazole

The title compound was prepared in a manner similar to that described inExample 88 using 5-bromo-1H-benzo[d]imidazole and2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine.MS (ESI): mass calcd. for C₂₃H₁₅FN₄O, 382.12; m/z found, 383.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 9.31 (s, 1H), 8.52-8.45 (d, J=4.9, 2H), 7.95(s, 1H), 7.92-7.87 (d, J=8.6, 1H), 7.79-7.70 (d, J=8.6, 1H), 7.59-7.55(dd, J=7.7, 1.7, 1H), 7.55-7.47 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.32(dd, J=12.0, 1.7, 1H), 7.30-7.23 (dd, J=8.1, 1.2, 1H), 7.13-7.08 (t,J=4.8, 1H).

Example 544

6-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-3H-imidazo[4,5-b]pyridine

The title compound was prepared in a manner similar to that described inExample 88 using 6-bromo-3H-imidazo[4,5-b]pyridine and2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine.MS (ESI): mass calcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.55-8.52 (m, 1H), 8.51-8.47 (d, J=4.9, 2H),8.43 (s, 1H), 8.19-8.14 (t, J=1.7, 1H), 7.59-7.55 (dd, J=7.7, 1.8, 1H),7.55-7.47 (m, 2H), 7.46-7.40 (m, 2H), 7.39-7.33 (dd, J=11.9, 1.7, 1H),7.30-7.25 (dd, J=8.0, 1.2, 1H).

Example 545

5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4-methylpyrimidine. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.37 (d, J=5.1, 1H), 8.32 (d, J=1.6, 1H), 8.00 (d, J=1.6,1H), 7.82 (m, 1H), 7.56 (dd, J=7.5, 1.7, 1H), 7.51-7.44 (m, 1H),7.41-7.24 (m, 4H), 7.05 (d, J=5.1, 1H), 6.70 (s, 2H), 2.34 (s, 3H).

Example 546

5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4-methylpyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.44 (s, 2H), 8.39 (d, J=5.1, 1H), 7.57-7.44(m, 3H), 7.41-7.31 (m, 3H), 7.25 (d, J=7.2, 1H), 7.07 (d, J=4.9, 1H),6.89 (s, 2H), 2.35 (s, 3H).

Example 547

5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyrimidine. MS(ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.76 (d, J=5.8, 1H), 8.29-8.24 (m, 1H), 7.95(d, J=1.5, 1H), 7.78 (m, 1H), 7.58 (dd, J=7.5, 1.8, 1H), 7.54-7.48 (m,1H), 7.45 (m, 1H), 7.39 (dd, J=8.0, 1.3, 1H), 7.27 (m, 3H), 6.66 (s,2H).

Example 548

5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (d, J=5.7, 1H), 8.37 (m, 2H), 7.57 (dd,J=7.5, 1.8, 1H), 7.48 (m, 3H), 7.39 (dd, J=8.0, 1.3, 1H), 7.33-7.22 (m,3H), 6.85 (s, 2H).

Example 549

5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-5-methoxypyrimidine. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O₂, 389.13; m/z found, 390.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.35 (s, 1H), 7.55 (m, 2H), 7.46 (m, 1H),7.42-7.32 (m, 3H), 7.22 (d, J=8.0, 1H), 6.89 (s, 2H), 3.83 (s, 3H).

Example 550

5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-5-methoxypyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₆FN₅O₂, 389.13; m/z found, 390.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.30-8.26 (m, 3H), 7.96 (d, J=1.5, 1H), 7.78(m, 1H), 7.52 (dd, J=7.6, 1.7, 1H), 7.46-7.39 (m, 1H), 7.37-7.26 (m,3H), 7.19 (dd, J=8.1, 1.2, 1H), 6.66 (s, 2H), 3.76 (d, J=1.9, 3H).

Example 551

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine. MS(ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.49 (s, 1H), 8.48 (s, 1H), 8.30-8.27 (d, J=1.7,1H), 8.13-8.10 (d, J=1.4, 1H), 7.89-7.84 (m, 1H), 7.77-7.73 (m, 1H),7.73-7.68 (m, 1H), 7.63-7.59 (d, J=2.0, 1H), 7.42-7.38 (dd, J=8.1, 1.7,1H), 7.37-7.33 (dd, J=12.4, 1.7, 1H), 7.14-7.07 (t, J=4.9, 1H).

Example 552

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine. MS(ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.50 (s, 1H), 8.49 (s, 1H), 8.45-8.43 (d, J=1.4,2H), 7.76-7.73 (m, 1H), 7.73-7.69 (m, 1H), 7.62-7.60 (d, J=1.6, 1H),7.49-7.44 (m, 1H), 7.41-7.38 (m, 1H), 7.38-7.34 (dd, J=11.9, 1.7, 1H),7.14-7.11 (t, J=4.8, 1H).

Example 553

5-[3-Fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 1-bromo-2-methoxy-4-(trifluoromethyl)benzene. MS (ESI):mass calcd. for C₁₈H₁₃F₄N₃O, 363.10; m/z found, 364.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.39-8.37 (m, 1H), 8.11-8.08 (d, J=1.5, 1H),7.93-7.87 (m, 1H), 7.55-7.52 (m, 1H), 7.45-7.37 (m, 2H), 7.36-7.31 (m,2H), 3.90 (s, 3H).

Example 554

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol

To a stirred solution of5-[3-fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine(370 mg, 1.02 mmol) in dry dichloromethane (9.8 mL) at −78° Celsius, wasadded a boron tribromide in dichloromethane (3.1 mL, 1 M). The flask wasslowly warmed to rt and stirred overnight. The reaction was poured intosat. NH₄Cl and the pH adjusted to 8 with saturated NaHCO₃. The resultantmixture was extracted with DCM (3×30 mL) and the combined extracts driedover Na₂SO₄, filtered and concentrated to dryness. The crude product waspurified by HPLC to give the title compound. MS (ESI): mass calcd. forC₁₇H₁₁F₄N₃O, 349.08; m/z found, 350.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.41-8.35 (m, 1H), 8.17-8.10 (d, J=1.5, 1H), 7.99-7.88 (m, 1H),7.56-7.46 (m, 3H), 7.22-7.19 (m, 1H), 7.19-7.17 (d, J=1.7, 1H).

Example 555

4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine

To a 5 mL vial were added a stir bar,4′-(5-aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol (40mg, 0.12 mmol), 4-chloropyrimidin-2-amine (17.8 mg, 0.14 mmol), DMSO (1mL) and Cs₂CO₃ (52 mg, 0.16 mmol). The vial was flushed with nitrogenand heated for 15 hours at 120° Celsius. The reaction was diluted with 5mL of ethyl acetate and 5 mL of brine. The aqueous layer was thenextracted with ethyl acetate (3×10 mL), the combined organic extractsdried over Na₂SO₄, and concentrated to dryness. The crude product waspurified by HPLC to give the title compound. MS (ESI): mass calcd. forC₂₁H₁₄F₄N₆O, 442.12; m/z found, 443.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.34 (s, 1H), 8.09-8.07 (d, J=1.4, 1H), 8.07-8.05 (d, J=7.0, 1H),7.96-7.88 (m, 1H), 7.82-7.74 (d, J=1.6, 2H), 7.71 (s, 1H), 7.41-7.37(dd, J=8.1, 1.7, 1H), 7.37-7.32 (dd, J=12.4, 1.7, 1H), 6.64-6.56 (d,J=7.0, 1H).

Example 556

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 555 using 2-chloropyrimidin-4-amine. MS (ESI): mass calcd. forC₂₁H₁₄F₄N₆O, 442.12; m/z found, 443.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.38-8.32 (m, 1H), 8.10-8.04 (d, J=1.5, 1H), 7.98-7.90 (m, 1H),7.89-7.84 (d, J=6.9, 1H), 7.78 (s, 3H), 7.40-7.37 (dd, J=8.1, 1.8, 1H),7.37-7.33 (dd, J=12.4, 1.7, 1H), 6.36-6.26 (d, J=6.9, 1H).

Example 557

5-[3-Fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]methoxy}biphenyl-4-yl]-pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using(2-((2-bromo-5-(trifluoromethyl)phenoxy)methoxy)ethyl)trimethylsilaneand5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₃H₂₅F₄N₃O₂Si, 479.17; m/z found, 480.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.55-8.48 (m, 2H), 7.60-7.51 (m, 3H),7.48-7.36 (m, 3H), 5.33-5.29 (d, J=1.0, 2H), 3.73-3.66 (m, 2H),0.93-0.84 (t, J=8.0, 2H), −0.03-−0.07 (m, 9H).

Example 558

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol

To a stirred solution of5-[3-fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]-methoxy}-biphenyl-4-yl]pyrimidin-2-aminein 14 mL of THF were added water (1.40 mL), acetic acid (1.40 mL) andhydrochloric acid (0.43 mL, 6 N). The reaction was stirred overnight at65° Celsius, before diluting with ethyl acetate (20 mL) and water (20mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) andthe combined organic extracts dried over Na₂SO₄, and concentrated todryness. The crude product was purified by FCC to provide the titlecompound. MS (ESI): mass calcd. for C₁₇H₁₁F₄N₃O, 349.08; m/z found,350.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (s, 2H), 7.61-7.48 (m, 4H),7.23-7.19 (dd, J=8.3, 1.8, 1H), 7.19-7.17 (d, J=1.6, 1H).

Example 559

5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 555 using 2-chloropyrimidin-4-amine and4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol.MS (ESI): mass calcd. for C₂₁H₁₄F₄N₆O, 442.12; m/z found, 443.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.46 (s, 2H), 7.80-7.74 (m, 1H), 7.74-7.67 (m,1H), 7.67-7.62 (m, 1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.44-7.31 (dd,J=17.9, 10.0, 2H), 6.20-6.08 (dd, J=6.0, 1.4, 1H).

Example 560

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 555 using 4-chloropyrimidin-2-amine and4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol.MS (ESI): mass calcd. for C₂₁H₁₄F₄N₆O, 442.12; m/z found, 443.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.51-8.43 (d, J=1.3, 2H), 8.06-7.94 (d, J=5.7,1H), 7.72-7.69 (m, 1H), 7.69-7.66 (m, 1H), 7.55 (s, 1H), 7.52-7.47 (m,1H), 7.39-7.31 (m, 2H), 6.31-6.03 (d, J=5.7, 1H).

Example 561

5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 555 using 6-chloropyrimidin-4-amine and4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol.MS (ESI): mass calcd. for C₂₁H₁₄F₄N₆O, 442.12; m/z found, 443.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.60-8.54 (d, J=1.3, 2H), 8.11-8.07 (d, J=0.9,1H), 7.82-7.69 (m, 2H), 7.60 (s, 1H), 7.59-7.52 (m, 1H), 7.47-7.36 (m,2H), 5.95-5.88 (d, J=0.9, 1H).

Example 562

5-[3-Fluoro-2′,4′-bis(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using1-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)-4-methylpiperazine. MS(ESI): mass calcd. for C₁₈H₁₀F₇N₃, 401.08; m/z found, 402.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.43-8.39 (m, 1H), 8.11-8.07 (m, 2H), 8.04-8.00(d, J=8.2, 1H), 7.99-7.93 (m, 1H), 7.71-7.65 (d, J=8.0, 1H), 7.29-7.25(d, J=8.2, 1H), 7.25-7.20 (d, J=11.6, 1H).

Example 563

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 2-bromo-5-(trifluoromethyl)benzonitrile. MS (ESI): masscalcd. for C₁₈H₁₀F₄N₄, 358.08; m/z found, 359.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.45 (s, 1H), 8.23 (s, 1H), 8.11-8.08 (m, 1H), 8.08-8.03 (m,2H), 7.91-7.84 (d, J=8.2, 1H), 7.58-7.49 (m, 2H).

4′-Acetyl-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to thosedescribed in Example 1 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronicacid and 1-(4-bromo-2-fluorophenyl)ethanone. ¹H NMR (500 MHz, CDCl₃) δ8.19 (dd, J=7.9, 1.3, 1H), 7.95 (m, 1H), 7.63-7.57 (m, 1H), 7.57-7.52(m, 1H), 7.38-7.30 (m, 2H), 7.28 (dd, J=7.5, 1.3, 1H), 2.70 (d, J=4.9,3H), 1.05 (m, 9H).

4′-Acetyl-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to thosedescribed in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. forC₁₈H₂₀FNO₃S, 349.11; m/z found, 350.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.05 (dd, J=7.9, 1.2, 1H), 7.92 (m, 1H), 7.61-7.56 (m, 1H), 7.55-7.49(m, 1H), 7.29-7.27 (m, 2H), 7.25-7.24 (m, 1H), 2.95 (q, J=7.1, 4H), 2.69(d, J=4.9, 3H), 1.01 (t, J=7.1, 6H).

1-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]ethanone

The title compound was prepared using conditions analogous to thosedescribed in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and1-(2-bromo-phenylsulfonyl)pyrrolidine. MS (ESI): mass calcd. forC₁₈H₁₈FNO₃S, 347.10; m/z found, 348.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.10 (dd, J=7.9, 1.3, 1H), 7.95-7.89 (m, 1H), 7.63-7.58 (m, 1H),7.58-7.51 (m, 1H), 7.30-7.27 (m, 2H), 7.26-7.25 (m, 1H), 2.98-2.90 (m,4H), 2.69 (d, J=4.9, 3H), 1.76-1.67 (m, 4H).

Example 564

5-{5-[2-(Pyrimidin-2-yloxy)-4-(trifluoromethyl)phenyl]pyrridn-2-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine and5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₃F₃N₆O, 410.11; m/z found, 411.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 2H), 8.73 (d, J=2.3, 1H), 8.50 (d,J=4.8, 2H), 8.04 (dd, J=8.3, 2.4, 1H), 7.85 (d, J=8.4, 1H), 7.81-7.72(m, 2H), 7.66 (d, J=1.7, 1H), 7.13 (t, J=4.8, 1H).

Example 565

4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-5-(trifluoromethyl)phenoxy}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidin-2-amineand5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₄F₃N₇O, 425.12; m/z found, 426.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 2H), 8.67 (dd, J=2.3, 0.8, 1H), 7.99(d, J=5.6, 1H), 7.95 (dd, J=8.3, 2.3, 1H), 7.81 (dd, J=8.2, 0.9, 1H),7.76-7.69 (m, 2H), 7.59 (s, 1H), 6.18 (d, J=5.8, 1H).

Example 566

5-{5-[2-(Pyrimidin-2-yloxy)phenyl]pyridin-2-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidine and5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₄N₆O, 342.12; m/z found, 343.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.97 (s, 2H), 8.70 (dd, J=2.3, 0.8, 1H), 8.48 (d,J=4.8, 2H), 8.06 (dd, J=8.3, 2.3, 1H), 7.85 (dd, J=8.3, 0.9, 1H), 7.58(dd, J=7.6, 1.8, 1H), 7.56-7.50 (m, 1H), 7.48-7.41 (m, 1H), 7.30 (dd,J=8.0, 1.2, 1H), 7.10 (t, J=4.8, 1H).

Example 567

4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenoxy}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)pyrimidin-2-amine and5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₅N₇O, 357.13; m/z found, 358.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.91 (s, 2H), 8.68-8.59 (m, 1H), 8.03 (dd, J=6.9,0.9, 1H), 7.97-7.89 (m, 1H), 7.83 (d, J=8.3, 1H), 7.60-7.53 (m, 2H),7.52-7.44 (m, 1H), 7.35 (d, J=7.9, 1H), 6.53 (dd, J=6.9, 0.9, 1H).

Example 568

5-(5-{2-[(4-Aminopyrimidin-2-yl)oxy]phenyl}pyridin-2-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₅N₇O, 357.13; m/z found, 358.0 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.86 (s, 2H), 8.64 (dd, J=2.3, 0.8, 1H), 7.95(dd, J=8.3, 2.3, 1H), 7.78-7.72 (m, 2H), 7.53-7.45 (m, 2H), 7.38 (m,1H), 7.23 (dd, J=8.1, 1.2, 1H), 6.11 (d, J=5.9, 1H).

Example 569

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using (4-bromo-2-methylphenyl)boronic acid in Step A. MS(ESI): mass calcd. for C₂₁H₂₄N₄O₂S, 396.16; m/z found, 397.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.21-8.17 (dd, J=8.0, 1.3, 1H), 8.13-8.07 (m,2H), 7.61-7.54 (m, 1H), 7.52-7.47 (m, 1H), 7.47-7.39 (m, 3H), 7.36-7.31(dd, J=7.5, 1.4, 1H), 4.82 (s, 2H), 4.16-4.09 (m, 1H), 2.41 (s, 3H),1.05 (s, 9H).

Example 570

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methoxybiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using (4-bromo-2-methoxyphenyl)boronic acid in Step A. MS(ESI): mass calcd. for C₂₁H₂₄N₄O₃S, 412.16; m/z found, 413.3 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.51-8.45 (d, J=1.6, 1H), 8.21-8.16 (d, J=1.5,1H), 8.16-8.11 (dd, J=8.0, 1.3, 1H), 7.84-7.78 (d, J=7.9, 1H), 7.67-7.61(m, 1H), 7.58-7.54 (m, 1H), 7.45-7.38 (dd, J=7.6, 1.4, 1H), 7.32-7.25(d, J=1.6, 1H), 7.15-7.09 (dd, J=7.9, 1.6, 1H), 3.92 (s, 3H), 1.04 (s,9H).

Example 571

4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide Step A:5-(4-Bromophenyl)pyrazin-2-amine

(4-Bromophenyl)boronic acid (100 mg, 0.498 mmol) and5-bromopyrazin-2-amine (173 mg, 0.996 mmol) were added to a 5 mLsealable vial equipped with a stir bar. To this vial was added toluene(1.5 mL), ethanol (1.5 mL) and K₂CO₃(0.7 mL, 2 M). The solvent wassparged with argon for 10 min before adding Pd(PPh₃)₄ (17 mg, 0.004mmol), the vial sealed and the mixture stirred at 50° Celsius for 15hours. The reaction was cooled to rt and then diluted with ethyl acetate(50 mL) and water (50 mL) and the layers separated. The aqueous layerwas further extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried with Na₂SO₄ and concentrated to dryness. The crudematerial was purified FCC to give 5-(4-bromophenyl)pyrazin-2-amine. ¹HNMR (500 MHz, CDCl₃) δ 8.52-8.31 (d, J=1.5, 1H), 8.08-7.95 (d, J=1.6,1H), 7.86-7.71 (d, J=8.4, 2H), 7.63-7.49 (d, J=8.6, 2H), 4.70 (s, 2H).

Step B: 4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide

To a 5 mL sealable vial equipped with a stir bar were added5-(4-bromophenyl)pyrazin-2-amine (40 mg, 0.16 mmol),(2-(N-(tert-butyl)sulfamoyl)phenyl)-boronic acid (62 mg, 0.24 mmol),K₂CO₃ (66 mg, 0.48 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (12 mg, 0.016 mmol). Thevial was then sealed, evacuated, backfilled with argon and charged withargon sparged DMSO (0.64 mL). The vial was heated at 70° Celsius for 15hours. The reaction mixture was cooled to rt diluted with ethyl acetate(2 mL) and water (2 mL), the layers separated and the aqueous layerfurther extracted with ethyl acetate (3×10 mL). The combined organicextracts were then dried with Na₂SO₄ and concentrated to dryness. Thecrude product was purified by HPLC to give the title compound. MS (ESI):mass calcd. for C₂₀H₂₂N₄O₂S, 382.15; m/z found, 383.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.48-8.39 (d, J=1.5, 1H), 8.23-8.18 (dd, J=8.0, 1.4,1H), 8.18-8.15 (d, J=1.4, 1H), 7.99-7.95 (d, J=8.4, 1H), 7.65-7.61 (m,2H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 1H), 7.38-7.31 (dd, J=7.5, 1.4,1H), 3.70 (s, 1H), 1.25 (s, 1H), 1.03 (s, 9H).

Example 572

4′-(5-Aminopyrazin-2-yl)-N,N-dimethylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid in StepB. MS (ESI): mass calcd. for C₁₈H₁₈N₄O₂S, 354.12; m/z found, 355.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.60-8.32 (d, J=1.5, 1H), 8.09-8.05(dd, J=8.0, 1.4, 1H), 8.05-8.02 (d, J=1.5, 1H), 7.95-7.86 (m, 2H),7.72-7.62 (m, 1H), 7.61-7.53 (m, 1H), 7.48-7.41 (m, 2H), 7.41-7.35 (dd,J=7.6, 1.4, 1H), 2.40 (s, 6H).

Example 573

5-[2′-(Morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 571 using (2-(morpholinosulfonyl)phenyl)boronic acid in in StepB. MS (ESI): mass calcd. for C₂₀H₂₀N₄O₃S, 396.13; m/z found, 397.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.60-8.55 (d, J=1.4, 1H), 8.05-8.00(dd, J=8.0, 1.3, 1H), 8.00-7.94 (m, 3H), 7.78-7.73 (m, 1H), 7.69-7.62(m, 1H), 7.49-7.39 (m, 3H), 6.61 (s, 2H), 2.76-2.68 (t, J=4.7, 3H).

Example 574

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using (4-bromo-3-fluorophenyl)boronic acid in Step A. MS(ESI): mass calcd. for C₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.50-8.43 (d, J=1.5, 1H), 8.18-8.12 (dd, J=8.0,1.4, 1H), 8.05-8.02 (d, J=1.5, 1H), 7.74-7.67 (m, 2H), 7.66-7.61 (m,1H), 7.60-7.53 (m, 1H), 7.47-7.39 (m, 1H), 7.39-7.32 (dd, J=7.5, 1.5,1H), 1.11 (s, 9H).

Example 575

4′-(5-Aminopyrazin-2-yl)-2′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 571 using (4-bromo-3-fluorophenyl)boronic acid in Step A andusing (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid in Step B. MS (ESI):mass calcd. for C₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.2 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.51-8.41 (d, J=1.5, 1H), 8.10-8.06 (dd, J=8.0, 1.4,1H), 8.06-8.02 (d, J=1.5, 1H), 7.75-7.67 (m, 3H), 7.67-7.59 (m, 1H),7.43-7.39 (m, 1H), 7.39-7.34 (m, 1H), 2.49 (s, 6H). The title

Example 576

4′-(2-Amino-1,3-oxazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamideStep A: 4-(4-Bromo-2-fluorophenyl)oxazol-2-amine

A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethanone (53 mg, 0.18mmol) and urea (10.6 mg, 0.18 mmol) in CH₃CN (0.7 mL) was heated at 80°Celsius for 18 hours. The mixture was cooled to rt and made basic withNaOH (2 N). The resulting solution was extracted with EtOAc and theextract was dried (Na₂SO₄), filtered, and concentrated to dryness. Theresidue was purified using FCC to give4-(4-bromo-2-fluorophenyl)oxazol-2-amine (37 mg, 82%). MS (ESI): masscalcd. for C₉H₆BrFN₂O, 255.96; m/z found, 257.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.78 (m, 1H), 7.58 (d, J=4.3, 1H), 7.36-7.32 (m, 1H), 7.28 (dd,J=10.5, 1.9, 1H), 4.60 (s, 2H).

Step B

The title compound was prepared using methods described in Example 427using 4-(4-bromo-2-fluorophenyl)oxazol-2-amine and(2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₁₉H₂₀FN₃O₃S, 389.12; m/z found, 390.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.18 (dd, J=7.9, 1.4, 1H), 7.98 (m, 1H), 7.66 (d, J=4.2, 1H),7.57 (m, 1H), 7.54-7.48 (m, 1H), 7.38-7.30 (m, 3H), 4.63 (s, 2H), 3.64(s, 1H), 1.03 (s, 9H).

Example 577

4′-(2-Amino-1,3-thiazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

A solution of 4′-acetyl-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide(100 mg, 0.29 mmol), iodine (94.6 mg, 0.37 mmol), thiourea (44.01, 0.57mmol) in EtOH (1.1 mL) was heated at 100 Celcius for 48 h. The reactionmixture was cooled to rt and the precipitate collected by filtrationthus providing the title compound. MS (ESI): mass calcd. forC₁₉H₂₀FN₃O₂S₂, 405.10; m/z found, 406.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 8.71 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.59 (m, 1H), 7.54(dd, J=11.6, 3.8, 1H), 7.44 (dd, J=12.1, 1.6, 1H), 7.38 (dd, J=8.1, 1.7,1H), 7.33 (dd, J=7.5, 1.3, 1H), 6.96 (d, J=1.3, 1H), 1.08 (s, 9H).

Example 578

4′-(2-Amino-1,3-thiazol-4-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using4′-acetyl-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide. MS (ESI): masscalcd. for C₁₉H₂₀FN₃O₂S₂, 405.10; m/z found, 406.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.64 (s, 2H), 8.06 (dd, J=7.9, 1.2, 1H), 7.93 (m, 1H),7.59 (td, J=7.5, 1.4, 1H), 7.52 (m, 1H), 7.39-7.28 (m, 3H), 6.95 (d,J=1.1, 1H), 2.97 (q, J=7.2, 4H), 1.02 (t, J=7.1, 6H).

Example 579

4-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-1,3-thiazol-2-amine

The title compound was prepared using methods analogous to thosedescribed in Example 577 using1-[3-fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]ethanone. MS(ESI): mass calcd. for C₁₉H₁₈FN₃O₂S₂, 403.08; m/z found, 404.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J=6.7, 1H), 7.91 (m, 1H), 7.61 (td,J=7.5, 1.4, 1H), 7.54 (m, 1H), 7.41-7.28 (m, 3H), 6.94 (d, J=1.2, 1H),2.95 (t, J=6.7, 4H), 1.85-1.64 (m, 4H).

Example 580

N-tert-Butyl-3′-fluoro-4′-(8-fluoroimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 3-fluoropyridin-2-amine. MS (ESI): masscalcd. for C₂₃H₂₁F₂N₃O₂S, 441.13; m/z found, 442.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.60-8.51 (m, 1H), 8.51-8.45 (m, 2H), 8.20 (d, J=6.6, 1H),7.68-7.53 (m, 3H), 7.53-7.48 (m, 2H), 7.38 (d, J=7.6, 2H), 1.16-1.08 (m,9H).

Example 581

4′-(5-Aminoimidazo[1,2-a]pyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using pyridine-2,3-diamine. MS (ESI): masscalcd. for C₂₃H₂₃FN₄O₂S, 438.15; m/z found, 439.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.19-8.11 (m, 2H), 7.99-7.95 (m, 1H), 7.61 (dd, J=8.1,6.8, 1H), 7.55 (m, 1H), 7.38-7.32 (m, 3H), 7.20-7.12 (m, 2H), 6.36 (d,J=8.5, 1H), 1.13 (s, 9H).

Example 582

2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 6-aminonicotinamide. MS (ESI): masscalcd. for C₂₄H₂₃FN₄O₃S, 466.15; m/z found, 467.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.91 (s, 1H), 8.24 (d, J=6.5, 1H), 8.14-8.03 (m, 2H),7.93-7.84 (m, 2H), 7.64-7.52 (m, 3H), 7.49-7.42 (m, 1H), 7.35 (d,J=11.7, 1H), 6.49-6.40 (m, 1H), 1.28-1.20 (m, 9H).

Example 583

2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 6-aminonicotinamide. MS (ESI): masscalcd. for C₂₄H₂₃FN₄O₃S, 466.15; m/z found, 467.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.91 (s, 1H), 8.24 (d, J=6.5, 1H), 8.14-8.03 (m, 2H),7.93-7.84 (m, 2H), 7.64-7.52 (m, 3H), 7.49-7.42 (m, 1H), 7.35 (d,J=11.7, 1H), 6.49-6.40 (m, 1H), 1.28-1.20 (m, 9H).

Example 584

N-tert-Butyl-4′-(5-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 2-amino-4-cyanopyridine. MS (ESI): masscalcd. for C₂₄H₂₁FN₄O₂S, 448.14; m/z found, 449.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.38-8.33 (m, 2H), 8.32-8.25 (m, 2H), 8.20 (dd, J=8.0,1.2, 1H), 7.61 (m, 1H), 7.54 (td, J=7.8, 1.4, 1H), 7.51-7.45 (m, 1H),7.42 (dd, J=8.0, 1.7, 1H), 7.35 (dd, J=7.5, 1.3, 1H), 7.16 (dd, J=7.0,1.6, 1H), 1.07 (s, 9H).

Example 585

N-tert-Butyl-4′-(6-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 2-amino-5-cyanopyridine. MS (ESI): masscalcd. for C₂₄H₂₁FN₄O₂S, 448.14; m/z found, 449.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.70 (s, 1H), 8.28 (m, 1H), 8.25-8.19 (m, 2H), 8.14 (d,J=9.4, 1H), 7.61 (m, 1H), 7.58-7.52 (m, 2H), 7.51-7.47 (m, 1H), 7.43(dd, J=8.0, 1.7, 1H), 7.35 (dd, J=7.5, 1.3, 1H), 1.07 (s, 9H).

Example 586

N-tert-Butyl-3′-fluoro-4′-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]biphenyl-2-sulfonamide

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 2-amino-5-(trifluoromethyl)pyridine. MS(ESI): mass calcd. for C₂₄H₂₁F₄N₃O₂S, 491.13; m/z found, 492.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 8.31 (dd, J=16.6, 8.7, 2H), 8.25(d, J=2.8, 1H), 8.20 (dd, J=8.0, 1.2, 1H), 7.72-7.66 (m, 1H), 7.65-7.59(m, 1H), 7.59-7.49 (m, 2H), 7.43 (dd, J=8.0, 1.7, 1H), 7.35 (dd, J=7.5,1.2, 1H), 1.05 (m, 9H).

Example 587

Ethyl2-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-5-carboxylate

The title compound was prepared using methods analogous to thosedescribed in Example 577 using 2-aminonicotinic acid. The ethyl esterwas formed as a result of carrying out the reaction in EtOH. MS (ESI):mass calcd. for C₂₆H₂₆FN₃O₄S, 495.16; m/z found, 496.3 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.62-8.55 (m, 1H), 8.36 (d, J=6.5, 1H), 8.23-8.18 (m,2H), 8.01 (d, J=7.3, 1H), 7.62-7.55 (m, 1H), 7.55-7.49 (m, 1H),7.44-7.33 (m, 3H), 6.91 (m, 1H), 4.54 (dd, J=14.2, 7.1, 2H), 1.51 (t,J=7.2, 3H), 1.03 (s, 9H).

Example 588

N-tert-Butyl-3′-fluoro-4′-(5-methoxyimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamideStep A: 2-(4-Bromo-2-fluorophenyl)-5-methoxyimidazo[1,2-a]pyridine

A solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethanone (100 mg, 0.34mmol) and 2-amino-3-methoxypyridine (42 mg, 0.34 mmol) in EtOH (0.8 mL)was heated at 90° Celsius for 24 hours. The reaction mixture was cooledto rt and diluted with water.

The resultant precipitate was collected by filtration to provide2-(4-bromo-2-fluorophenyl)-5-methoxyimidazo[1,2-a]pyridine (35 mg, 32%)which was used without further purification.

Step B

The title compound was prepared using methods analogous to thosedescribed in Example 88 using2-(4-bromo-2-fluorophenyl)-5-methoxyimidazo[1,2-a]pyridine and2-(tert-butylamino)sulfonylphenylboronic acid. MS (ESI): mass calcd. forC₂₄H₂₄FN₃O₃S, 453.15; m/z found, 454.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.58 (m, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 8.10 (d, J=3.9, 1H), 7.81 (dd,J=6.7, 0.9, 1H), 7.60-7.55 (m, 1H), 7.54-7.48 (m, 1H), 7.43 (dd, J=12.1,1.7, 1H), 7.38-7.32 (m, 2H), 6.73 (dd, J=7.6, 6.7, 1H), 6.50 (d, J=7.6,1H), 4.07 (s, 3H), 3.68 (s, 1H), 1.02 (s, 9H).

5-(4-Bromophenyl)pyrazin-2-amine

5-Bromopyrazin-2-amine (173 mg, 0.99 mmol) and (4-bromophenyl)boronicacid (100 mg, 0.490 mmol) were placed in a sealable vial followed bytoluene (1.5 mL), ethanol (1.5 mL), and K₂CO₃ (0.7 mL, 2 M). Theresultant mixture was then sparged with argon for 10 minutes beforeadding tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.15 mmol), andheating at 50° Celsius. Reaction progress was monitored by LCMS. Oncethe reaction was complete, the reaction mixture was cooled to rt,diluted with EtOAc, filtered through Celite, and the resultant filtrateconcentrated to dryness. The crude product was purified by FCC toprovide the title compound. ¹H NMR (500 MHz, CDCl₃) δ 8.52-8.31 (d,J=1.5, 1H), 8.08-7.95 (d, J=1.6, 1H), 7.86-7.71 (d, J=8.4, 2H),7.63-7.49 (d, J=8.6, 2H), 4.81-4.61 (s, 2H).

5-(4-Bromo-2-methylphenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HZ using (4-bromo-2-methylphenyl)boronic acid. ¹H NMR(500 MHz, CD₃OD) δ 8.01-7.97 (m, 2H), 7.47 (dd, J=1.9, 0.9, 1H),7.43-7.38 (m, 1H), 7.23 (d, J=8.2, 1H), 2.31 (s, 3H).

5-(4-Bromo-2-methoxyphenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that describedIntermediate HZ using (4-bromo-2-methoxyphenyl)boronic acid.

Example 589

5-[2′-(Methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

5-(4-Bromophenyl)pyrazin-2-amine (51 mg, 0.20 mmol),(2-(methylsulfonyl)phenyl) boronic acid (61 mg, 0.31 mmol), K₂CO₃ (85mg, 0.61 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (15 mg, 0.020 mmol) were weighedinto a sealable vial containing a stir-bar. The vial was sealed andevacuated before backfilling with argon and adding deoxygenated DMSO(0.8 mL). The vial was heated at 70° Celsius for 3 hours by which pointthe starting material had been consumed. The vial was cooler to rt,diluted with MeOH (1 mL), filtered with a syringe filter, and thefiltrate subjected to HPLC purification to provide the title compound.MS (ESI): mass calcd. for C₁₇H₁₅N₃O₂S, 325.39; m/z found, 326.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J=8.1, 1.4, 2H), 8.26 (dd, J=8.0,1.4, 1H), 8.00-7.90 (m, 2H), 7.74-7.64 (m, 1H), 7.64-7.56 (m, 3H), 7.41(dd, J=7.5, 1.4, 1H), 2.70 (s, 3H).

Example 590

5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 589 using 5-(4-bromo-2-methylphenyl)pyrazin-2-amine. MS (ESI):mass calcd. for C₁₈H₁₇N₃O₂S, 339.42; m/z found, 340.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.25 (dd, J=8.0, 1.4, 1H), 8.20 (d, J=1.5, 1H), 8.11(d, J=1.6, 1H), 7.70-7.63 (m, 1H), 7.60-7.54 (m, 1H), 7.49-7.45 (m, 1H),7.43-7.36 (m, 3H), 4.75 (s, 2H), 2.71 (s, 3H), 2.45 (s, 3H).

Example 591

4′-(5-Aminopyrazin-2-yl)-N,N,3′-trimethylbiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 589 using 5-(4-bromo-2-methylphenyl)pyrazin-2-amine and(2-(N,N-dimethylsulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₁₉H₂₀N₄O₂S, 368.46; m/z found, 369.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.16 (d, J=1.5, 1H), 8.12 (dd, J=8.0, 1.3, 1H), 8.10 (d, J=1.5, 1H),7.60-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.43 (d, J=7.8, 1H), 7.35-7.29 (m,3H), 4.77 (s, 2H), 2.44 (s, 3H), 2.42 (s, 6H).

Example 592

4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 589 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and5-(4-bromo-2-methoxyphenyl)pyrazin-2-amine. After the coupling, thetert-butyl group and methyl group were removed by treating a solutionconsisting of4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-methoxy-[1,1′-biphenyl]-2-sulfonamide(48 mg, 0.12 mmol) and DCM (2 mL), with BBr₃ (0.14 mL, 1 M in DCM) at−78° Celsius. The reaction mixture was warmed to room temperature. Afterthe starting material was consumed the reaction mixture was poured intosaturated NH₄Cl (10 mL) and extracted with DCM (3×10 mL). The combinedorganic extracts were dried with sodium sulfate, filtered, andconcentrated to dryness. The resultant residue was subjected to HPLCpurification to provide the title compound. MS (ESI): mass calcd. forC₁₆H₁₄N₄O₃S, 342.38; m/z found, 343.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.71 (s, 1H), 8.18 (dd, J=7.9, 1.4, 1H), 7.93 (d, J=1.4, 1H), 7.80 (d,J=8.2, 1H), 7.64-7.57 (m, 1H), 7.57-7.48 (m, 1H), 7.39 (dd, J=7.6, 1.3,1H), 7.12 (dd, J=8.1, 1.9, 1H), 7.09-7.03 (m, 1H), 4.38 (s, 2H).

Example 593

N-[4′-(5-Aminopyrazin-2-yl)biphenyl-2-yl]methanesulfonamide

The title compound was prepared in a manner similar to that described inExample 589 using (2-(methylsulfonamido)phenyl)boronic acid. MS (ESI):mass calcd. for C₁₇H₁₆N₄O₂S, 340.41; m/z found, 341.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.38 (d, J=1.4, 1H), 8.26 (d, J=1.5, 1H), 8.03-7.94(m, 2H), 7.67 (dd, J=8.2, 1.1, 1H), 7.46 (d, J=8.3, 2H), 7.45-7.40 (m,1H), 7.33-7.29 (m, 1H), 7.26-7.23 (m, 1H), 6.49 (s, 1H), 2.93 (s, 3H).

Example 594

4′-(5-Aminopyrazin-2-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 589 using (2-sulfamoylphenyl)boronic acid. MS (ESI): mass calcd.for C₁₆H₁₄N₄O₂S, 326.38; m/z found, 327.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.40 (d, J=1.5, 1H), 8.22 (d, J=1.4, 1H), 8.13 (dd, J=8.0, 1.3,1H), 7.93 (d, J=8.3, 2H), 7.67-7.59 (m, 1H), 7.59-7.50 (m, 3H), 7.37(dd, J=7.6, 1.4, 1H).

Example 595

N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromoindolin-2-one. MS (ESI): mass calcd. forC₂₄H₂₃FN₂O₃S, 438.52; m/z found, 439.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.20 (dd, J=7.9, 1.4, 1H), 8.09 (s, 1H), 7.63-7.56 (m, 1H), 7.56-7.50(m, 1H), 7.50-7.41 (m, 3H), 7.39-7.36 (m, 1H), 7.35 (dd, J=7.6, 1.4,1H), 7.32 (dd, J=11.4, 1.8, 1H), 6.97 (d, J=7.9, 1H), 3.90 (s, 1H), 3.61(s, 2H), 1.08 (s, 9H).

Example 596

N-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 6-bromoquinazoline-2,4(1H,3H)-dione. MS (ESI): masscalcd. for C₂₄H₂₂FN₃O₄S, 467.52; m/z found, 468.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.30-8.21 (m, 1H), 8.14 (dd, J=8.1, 1.4, 1H), 7.97-7.88(m, 1H), 7.68-7.62 (m, 1H), 7.62-7.52 (m, 2H), 7.40 (dd, J=7.6, 1.4,1H), 7.36 (s, 1H), 7.35-7.32 (m, 1H), 7.29 (d, J=8.5, 1H), 1.08 (s, 9H).

Example 597

4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using 5-bromo-1H-indazol-3-amine. MS (ESI): mass calcd. forC₂₃H₂₃FN₄O₂S, 438.53; m/z found, 439.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.15 (dd, J=8.0, 1.3, 1H), 8.11 (s, 1H), 7.80 (d, J=8.6, 1H), 7.69-7.63(m, 1H), 7.63-7.55 (m, 2H), 7.49 (dd, J=8.8, 0.9, 1H), 7.40 (dd, J=7.6,1.4, 1H), 7.37-7.35 (m, 1H), 7.34 (dd, J=6.0, 1.6, 1H), 1.10 (s, 9H).

Example 598

3-Amino-6-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylicacid

The title compound was prepared in a manner similar to that described inExample 427 using 3-amino-6-bromopyrazine-2-carboxylic acid. MS (ESI):mass calcd. for C₂₁H₂₁FN₄O₄S, 444.49; m/z found, 445.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.50 (s, 1H), 8.13 (dd, J=8.0, 1.3, 1H), 7.89 (s,1H), 7.65 (td, J=7.5, 1.4, 1H), 7.56 (td, J=7.8, 1.4, 1H), 7.43 (d,J=7.4, 1H), 7.37-7.22 (m, 2H), 1.07 (s, 8H).

2-((2-Bromophenyl)sulfonyl)acetamide Step A:2-((2-Bromophenyl)thio)acetamide

To a 20 mL vial were added a stir-bar 2-chloroacetamide (783 mg, 8.37mmol) 2-bromthiophenol (1.00 mL, 8.32 mmol) N,N-diisopropylethyl amine(1.5 ml, 8.7 mmol), and dry THF (5 mL). The reaction mixture was stirredfor 4 days before concentrating and subjecting the crude product to FCCto afford the title compound. ¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (s, 1H),7.60 (dd, J=7.9, 1.4, 1H), 7.41-7.30 (m, 2H), 7.25 (s, 1H), 7.13-7.06(m, 1H), 3.69 (s, 2H).

Step B: 2-((2-Bromophenyl)sulfonyl)acetamide

To a 40 mL vial were added 2-((2-bromophenyl)thio)acetamide (1.00 g,4.06 mmol), Oxone (7.51 g, 12.2 mmol), methanol (12 mL) and water (15mL). The reaction mixture was stirred for 21 hours at which point it wasdiluted with ethyl acetate (25 mL) and washed with aqueous Na₂S₂O₃ (25mL). The organic and water layers were separated and the aqueous phasefurther extracted with ethyl acetate (3×25 mL). The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedto dryness. The crude product was subjected to FCC to provide the titlecompound. ¹H NMR (600 MHz, DMSO-d₆) δ 8.04-7.95 (m, 1H), 7.93-7.87 (m,1H), 7.72 (s, 1H), 7.68-7.60 (m, 2H), 7.39 (s, 1H), 4.41 (s, 2H).

2-((2-Bromophenyl)sulfonyl)-N,N-diethylacetamide

The title compound was prepared in a manner similar to that describedfor 2-((2-bromophenyl)sulfonyl)acetamide using2-chloro-N,N-diethylacetamide in Step A. ¹H NMR (600 MHz, DMSO-d₆) δ8.01-7.97 (m, 1H), 7.91-7.87 (m, 1H), 7.66-7.60 (m, 2H), 4.75 (s, 2H),3.47-3.39 (q, J=7.1, 2H), 3.25-3.14 (q, J=7.0, 2H), 1.18-1.09 (t, J=7.1,3H), 0.99-0.87 (t, J=7.0, 3H).

2-((2-Bromophenyl)sulfonyl)-1-morpholinoethanone

The title compound was prepared in a manner similar to that describedfor 2-((2-bromophenyl)sulfonyl)acetamide using2-chloro-1-morpholinoethanone in Step A. ¹H NMR (600 MHz, DMSO-d₆) δ8.06-8.01 (m, 1H), 7.93-7.88 (m, 1H), 7.68-7.60 (m, 2H), 4.84 (s, 2H),3.63-3.55 (m, 4H), 3.53-3.48 (dd, J=5.6, 4.0, 2H), 3.42-3.37 (d, J=5.2,2H).

Example 599

2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-((2-bromophenyl)sulfonyl)acetamide. MS (ESI): mass calcd. forC₁₈H₁₅FN₄O₃S, 386.41; m/z found, 387.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.9, 1.2, 1H), 7.80-7.72 (m, 1H),7.69-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.43 (dd, J=7.5, 1.3, 1H),7.39-7.30 (m, 2H).

Example 600

2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N-diethylacetamide

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-((2-bromophenyl)sulfonyl)-N,N-diethylacetamide. MS (ESI): masscalcd. for C₂₂H₂₃FN₄O₃S, 442.52; m/z found, 443.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.55 (d, J=1.4, 2H), 8.13 (dd, J=8.0, 1.3, 1H), 7.81-7.73(m, 1H), 7.71-7.63 (m, 1H), 7.62-7.55 (m, 1H), 7.44 (dd, J=7.6, 1.3,1H), 7.39 (dd, J=4.5, 1.7, 1H), 7.37 (dd, J=8.0, 1.3, 1H), 3.29-3.27 (m,4H), 1.07 (t, J=7.2, 3H), 1.04 (t, J=7.2, 3H).

Example 601

5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-((2-bromophenyl)sulfonyl)-1-morpholinoethanone. MS (ESI): masscalcd. for C₂₂H₂₁FN₄O₄S, 456.5; m/z found, 457.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.7, 1.3, 1H), 7.83-7.72(m, 1H), 7.72-7.63 (m, 1H), 7.58 (dd, J=8.5, 7.7, 1H), 7.45 (dd, J=7.2,1.2, 1H), 7.42-7.31 (m, 2H), 3.67-3.55 (m, 4H), 3.48 (t, J=4.8, 2H),3.39 (t, J=4.8, 2H).

Example 602

5,5′-(3,3″-Difluoro-1,1′:2′,1″-terphenyl-4,4″-diyl)dipyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 1-bromo-2-iodobenzene. MS (ESI): masscalcd. for C₂₆H₁₈F₂N₆, 452.47; m/z found, 453.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.35-8.30 (m, 2H), 8.02 (d, J=1.6, 2H), 7.78-7.70 (m, 2H), 7.49(s, 4H), 7.07 (dd, J=8.1, 1.7, 2H), 7.04 (dd, J=12.4, 1.7, 2H).

Example 603

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing 2-bromo-5-(trifluoromethyl)benzoicacid. MS (ESI): mass calcd. for C₁₈H₁₁F₄N₃O₂, 377.3; m/z found, 378.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.39 (s, 1H), 8.13 (s, 1H), 8.10 (s,1H), 8.00-7.84 (m, 2H), 7.65 (d, J=8.0, 1H), 7.28 (d, J=8.1, 1H), 7.24(d, J=12.6, 1H).

Example 604

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing2-bromo-5-(trifluoromethyl)benzaldehyde. MS (ESI): mass calcd. forC₁₈H₁₁F₄N₃O, 361.3; m/z found, 362.1 [M+H]⁺. The title compound canexist as either the aldehyde or the hydrate (gem-diol). Hydrate: ¹H NMR(400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.15 (d, J=1.5, 1H), 8.10-8.02 (m, 2H),7.70 (d, J=7.7, 1H), 7.49 (d, J=8.0, 1H), 7.36-7.27 (m, 2H), 5.47 (s,1H). Aldehyde: ¹H NMR (400 MHz, CD₃OD) δ 10.04 (s, 1H), 8.43 (s, 1H),8.39 (s, 1H), 8.26 (s, 1H), 8.02-7.94 (m, 2H), 7.77 (d, J=8.2, 1H),7.44-7.36 (m, 2H).

4-(2-Bromo-5-(trifluoromethyl)benzyl)morpholine

2-Bromo-5-(trifluoromethyl)benzaldehyde (266 mg, 1.05 mmol) andmorpholine (0.10 mL, 1.2 mmol) were dissolved in DCM (2 mL), stirred for20 minutes, and then treated with NaBH₄ (79 mg, 2.1 mmol). The reactionwas stirred overnight at rt, after which time, the reaction was quenchedby the slow addition of water (10 mL). The aqueous layer was furtherextracted with DCM (3×10 mL), dried over sodium sulfate, filtered, andconcentrated to dryness. The crude product was purified by FCC toprovide the title compound. ¹H NMR (500 MHz, CDCl₃) δ 7.77 (s, 1H), 7.67(d, J=8.3, 1H), 7.37 (d, J=8.3, 1H), 3.80-3.69 (m, 4H), 3.63 (d, J=1.7,2H), 2.59-2.49 (m, 4H).

tert-Butyl(1-(2-bromo-5-(trifluoromethyl)benzyl)piperidin-4-yl)carbamate

The title compound was prepared using analogous conditions to thosedescribed in Intermediate IF utilizing tert-butylpiperidin-4-ylcarbamate. ¹H NMR (500 MHz, CDCl₃) δ 7.82 (s, 1H),7.71-7.59 (m, 1H), 7.41 (d, J=8.3, 1H), 4.80 (s, 2H), 4.44 (s, 1H), 3.52(s, 1H), 3.14-2.89 (m, 2H), 2.65 (t, J=12.0, 2H), 1.93 (d, J=12.0, 2H),1.45 (s, 9H), 1.36-1.16 (m, 2H).

Example 605

5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing4-(2-bromo-5-(trifluoromethyl)benzyl)morpholine. MS (ESI): mass calcd.for C₂₂H₂₀F₄N₄O, 432.42; m/z found, 433.0 [M+H]⁺. ¹H NMR (400 MHz, MeOD)δ 8.43 (s, 1H), 8.21-8.11 (m, 2H), 8.11-8.04 (m, 1H), 7.90 (dd, J=8.2,1.8, 1H), 7.67 (d, J=8.1, 1H), 7.40-7.27 (m, 2H), 4.54 (s, 2H), 3.78 (s,4H), 3.07 (s, 4H).

Example 606

5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 6 utilizing tert-butyl(1-(2-bromo-5-(trifluoromethyl)benzyl)piperidin-4-yl)carbamate, followedby removal of the Boc group.

Removal of Boc group: To a stirred solution of tert-butyl(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)-[,1′-biphenyl]-2-yl)methyl)piperidin-4-yl)carbamate (83 mg, 0.15 mmol) inDCM (2.4 mL) was added TFA (0.64 mL, 8.4 mmol) at room temperature. Whenthe reaction had gone to completion, as followed by LCMS, the stir-barwas removed and the reaction mixture concentrated to dryness and theresultant residue subjected to HPLC purification to provide the titlecompound. MS (ESI): mass calcd. for C₂₃H₂₃F₄N₅, 445.47; m/z found, 446.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.44-8.40 (m, 1H), 8.13 (d, J=1.5,1H), 8.10-8.08 (m, 1H), 8.08-8.03 (m, 1H), 7.87 (d, J=8.2, 1H), 7.65 (d,J=8.1, 1H), 7.35 (dd, J=11.8, 1.7, 1H), 7.31 (dd, J=8.0, 1.7, 1H), 4.41(s, 2H), 3.42-3.35 (m, 2H), 3.29-3.26 (m, 1H), 2.82-2.69 (m, 2H),2.14-2.06 (m, 2H), 1.87-1.72 (m, 2H).

Example 607

2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol

The title compound was prepared using analogous conditions to thosedescribed in Intermediate IF using4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid and ethanolamine. MS (ESI): mass calcd. for C₂₀H₁₈F₄N₄O, 406.39;m/z found, 407.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.18(s, 1H), 8.12-8.01 (m, 2H), 7.86 (dd, J=8.1, 1.7, 1H), 7.65 (d, J=8.1,1H), 7.34 (dd, J=3.5, 1.6, 1H), 7.33-7.31 (m, 1H), 4.38 (s, 2H),3.78-3.63 (m, 2H), 3.09-3.00 (m, 2H).

2-(2-Bromophenoxy)-4,6-dimethylpyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-4,6-dimethylpyrimidine. ¹H NMR (400MHz, DMSO-d₆) δ 7.72 (dd, J=8.0, 1.4, 1H), 7.48-7.41 (m, 1H), 7.31 (dd,J=8.0, 1.6, 1H), 7.25-7.19 (m, 1H), 7.02 (s, 1H), 2.32 (s, 6H).

2-(2-Bromophenoxy)-6-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-6-methylpyrimidin-4-amine. ¹H NMR(400 MHz, DMSO-d₆) δ 7.63 (dd, J=8.0, 1.6, 1H), 7.40-7.34 (m, 1H), 7.21(dd, J=8.0, 1.6, 1H), 7.15-7.09 (m, 1H), 6.83 (s, 2H), 5.99 (s, 1H),2.07 (s, 3H).

2-(2-Bromophenoxy)-4-(trifluoromethyl)pyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-4-(trifluoromethyl)pyrimidine. ¹H NMR(400 MHz, DMSO-d₆) δ 9.03 (d, J=4.9, 1H), 7.86-7.73 (m, 2H), 7.55-7.42(m, 2H), 7.32-7.24 (m, 1H).

2-(2-bromophenoxy)pyrimidin-5-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloropyrimidin-5-amine. ¹H NMR (400 MHz,DMSO-d₆) δ d 7.98-7.94 (m, 2H), 7.71-7.66 (m, 1H), 7.45-7.37 (m, 1H),7.24-7.20 (m, 1H), 7.17-7.12 (m, 1H), 5.22 (s, 2H).

6-(2-Bromophenoxy)-2-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 6-chloro-2-methylpyrimidin-4-amine. ¹H NMR(400 MHz, DMSO-d₆) δ 7.64 (dd, J=8.3, 1.5, 1H), 7.47-7.33 (m, 1H), 7.17(ddd, J=7.2, 3.8, 1.3, 2H), 6.54 (s, 2H), 5.46 (s, 1H), 2.14 (s, 3H).

4-(2-Bromophenoxy)-6-cyclopropylpyrimidine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloro-6-cyclopropylpyrimidine. ¹H NMR (400MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.81-7.64 (m, 1H), 7.47-7.41 (m, 1H),7.36-7.28 (m, 1H), 7.26-7.21 (m, 1H), 7.14-7.09 (m, 1H), 2.16-2.08 (m,1H), 1.06-0.99 (m, 4H).

6-(2-Bromophenoxy)picolinonitrile

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 6-chloropicolinonitrile. ¹H NMR (400 MHz,DMSO-d₆) δ 8.13 (dd, J=8.5, 7.3, 1H), 7.82 (dd, J=7.3, 0.7, 1H), 7.77(dd, J=8.0, 1.5, 1H), 7.53-7.47 (m, 2H), 7.38 (dd, J=8.1, 1.6, 1H),7.32-7.25 (m, 1H).

6-(2-Bromophenoxy)nicotinonitrile

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 6-chloronicotinonitrile. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71-8.56 (m, 1H), 8.39-8.34 (m, 1H), 7.78-7.74 (m, 1H),7.51-7.46 (m, 1H), 7.39-7.33 (m, 2H), 7.30-7.24 (m, 1H).

4-(2-Bromophenoxy)-2-(trifluoromethyl)pyridine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloro-2-(trifluoromethyl)pyridine. ¹H NMR(400 MHz, DMSO-d₆) δ 8.60 (d, J=5.7, 1H), 7.80 (dd, J=8.0, 1.5, 1H),7.55-7.48 (m, 1H), 7.43-7.36 (m, 2H), 7.31 (m 1H), 7.03 (dd, J=5.7, 2.4,1H).

2-(2-Bromophenoxy)-6-(trifluoromethyl)pyridine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 2-chloro-6-(trifluoromethyl)pyridine. ¹H NMR(400 MHz, DMSO-d₆) δ 8.18-8.12 (m, 1H), 7.80-7.74 (m, 1H), 7.65 (d,J=7.4, 1H), 7.51-7.46 (m, 1H), 7.40-7.35 (m, 2H), 7.29-7.24 (m, 1H).

4-(2-Bromophenoxy)pyridin-2-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 4-chloropyridin-2-amine. ¹H NMR (400 MHz,DMSO-d₆) δ 8.14 (s, 1H), 7.82-7.72 (m, 2H), 7.50-7.41 (m, 1H), 7.29-7.18(m, 2H), 6.11 (dd, J=5.9, 2.3, 1H), 6.02 (s, 2H), 5.73 (d, J=2.3, 1H).

6-(2-Bromophenoxy)pyridin-3-amine

The title compound was prepared in a manner similar to that describedfor Intermediate HI using 6-chloropyridin-3-amine. ¹H NMR (400 MHz,DMSO-d₆) δ 7.63 (dd, J=8.0, 1.6, 1H), 7.40-7.34 (m, 1H), 7.21 (dd,J=8.0, 1.6, 1H), 7.15-7.09 (m, 1H), 6.83 (s, 2H), 5.99 (s, 1H), 2.07 (s,3H).

Example 608

5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4,6-dimethylpyrimidine. MS (ESI):mass calcd. for C₂₂H₁₈FN₅O, 387.15; m/z found, 388.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.96 (s, 1H), 7.78 (m, 1H), 7.50 (d,J=7.6, 1H), 7.42 (m 1H), 7.35-7.23 (m, 3H), 7.19 (d, J=7.8, 1H), 6.88(s, 1H), 6.66 (s, 2H), 2.22 (s, 6H).

Example 609

5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4,6-dimethylpyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₈FN₅O, 387.15; m/z found, 388.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 2H), 7.52-7.46 (m, 2H), 7.44-7.39(m, 1H), 7.35-7.25 (m, 3H), 7.18 (d, J=8.0, 1H), 6.90 (s, 1H), 6.85 (s,2H), 2.24 (s, 6H).

Example 610

5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyridine. MS(ESI): mass calcd. for C₂₂H₁₄F₄N₄O, 426.11; m/z found, 426.9 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=5.7, 1H), 8.30-8.25 (m, 1H), 7.96(d, J=1.5, 1H), 7.81 (m, 1H), 7.64 (dd, J=7.6, 1.8, 1H), 7.50 (m, 2H),7.39-7.29 (m, 4H), 7.04 (dd, J=5.7, 2.4, 1H), 6.68 (s, 2H).

Example 611

5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₄F₄N₄O, 426.11; m/z found, 426.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) 58.51 (d, J=5.7, 1H), 8.38 (d, J=1.5, 2H),7.62 (dd, J=7.6, 1.8, 1H), 7.56-7.42 (m, 3H), 7.38-7.30 (m, 4H), 7.04(dd, J=5.6, 2.4, 1H), 6.84 (s, 2H).

Example 612

5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4-(trifluoromethyl)pyrimidine. MS(ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO): δ 8.91 (d, J=4.9, 1H), 8.34-8.28 (m, 1H), 8.00 (d,J=1.4, 1H), 7.82 (m, 1H), 7.67 (d, J=4.9, 1H), 7.61-7.58 (m, 1H),7.55-7.50 (m, 1H), 7.47-7.39 (m, 2H), 7.34-7.29 (m, 2H), 6.70 (s, 2H).

Example 613

5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-4-(trifluoromethyl)pyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₃F₄N₅O, 427.11; m/z found, 428.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=4.9, 1H), 8.41 (d, J=1.4, 2H),7.69 (d, J=4.9, 1H), 7.60-7.57 (m, 1H), 7.55-7.50 (m, 2H), 7.46-7.38 (m,2H), 7.35-7.29 (m, 2H), 6.88 (s, 2H).

Example 614

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidin-5-amine. MS (ESI): masscalcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 375.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.35-8.31 (m, 1H), 8.01 (m, 1H), 7.92-7.89 (m, 2H), 7.83 (m,1H), 7.53 (dd, J=7.6, 1.7, 1H), 7.44-7.26 (m, 4H), 7.13 (dd, J=8.1, 1.2,1H), 6.68 (s, 2H), 5.16 (s, 2H).

Example 615

5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)pyrimidin-5-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₅FN₆O, 374.13; m/z found, 374.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d, J=1.5, 2H), 7.95-7.90 (m, 2H),7.57-7.50 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.34 (m,1H), 7.33-7.28 (m, 1H), 7.11 (dd, J=8.1, 1.2, 1H), 6.86 (s, 2H), 5.19(s, 2H).

Example 616

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-6-methylpyrimidin-4-amine. MS (ESI):mass calcd. for C₂₁H₁₇FN₆O, 388.15; m/z found, 389.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.98 (s, 1H), 7.82 (m, 1H), 7.47 (d,J=7.6, 1H), 7.42-7.25 (m, 4H), 7.13 (d, J=8.0, 1H), 6.80 (s, 2H), 6.66(s, 2H), 5.92 (s, 1H), 2.03 (s, 3H).

Example 617

5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 2-(2-bromophenoxy)-6-methylpyrimidin-4-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₇FN₆O, 388.15; m/z found, 389.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=1.2, 2H), 7.53 (t, J=8.2, 1H),7.49-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.34 (s, 1H), 7.33-7.30 (m, 1H),7.29-7.25 (m, 1H), 7.12 (d, J=8.0, 1H), 6.85 (s, 2H), 6.82 (s, 2H), 5.94(s, 1H), 2.04 (s, 3H).

Example 618

6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)picolinonitrile and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 383.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=1.4, 2H), 7.99 (dd, J=8.5, 7.4,1H), 7.71-7.67 (m, 1H), 7.56 (dd, J=7.6, 1.7, 1H), 7.55-7.46 (m, 2H),7.42-7.37 (m, 1H), 7.35-7.25 (m, 4H), 6.85 (s, 2H).

Example 619

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)picolinonitrile. MS (ESI): masscalcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 383.9 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.30-8.27 (m, 1H), 8.00-7.94 (m, 2H), 7.83-7.77 (m, 1H),7.68-7.64 (m, 1H), 7.57 (dd, J=7.6, 1.7, 1H), 7.52-7.45 (m, 1H),7.43-7.36 (m, 1H), 7.34-7.32 (m, 1H), 7.32-7.27 (m, 3H), 6.67 (s, 2H).

Example 620

5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)pyridin-3-amine. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O, 373.14; m/z found, 373.9 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.31 (s, 1H), 7.98 (d, J=1.2, 1H), 7.83 (m, 1H), 7.51-7.45(m, 2H), 7.42-7.31 (m, 3H), 7.23-7.18 (m, 1H), 7.03-6.99 (m, 1H),6.94-6.90 (m, 1H), 6.71 (d, J=8.6, 1H), 6.66 (s, 2H), 5.01 (s, 2H).

Example 621

5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)pyridin-3-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₆FN₅O, 373.14; m/z found, 373.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 2H), 7.53 (m, 1H), 7.50-7.45 (m,2H), 7.44-7.38 (m, 2H), 7.36-7.30 (m, 1H), 7.20 (t, J=7.4, 1H),7.06-7.00 (m, 1H), 6.91 (d, J=8.0, 1H), 6.85 (s, 2H), 6.72 (d, J=8.6,1H), 5.03 (s, 2H).

Example 622

5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)-2-methylpyrimidin-4-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₇FN₆O, 388.14; m/z found, 389.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=1.4, 2H), 7.54 (dd, J=7.6, 1.7,1H), 7.50-7.42 (m, 2H), 7.42-7.29 (m, 3H), 7.20 (dd, J=8.0, 1.2, 1H),5.43-5.31 (m, 1H), 2.25 (s, 3H).

Example 623

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-2-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)-2-methylpyrimidin-4-amine. MS (ESI):mass calcd. for C₂₁H₁₇FN₆O, 388.14; m/z found, 389.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.31 (dd, J=2.1, 1.6, 1H), 8.02 (d, J=1.5, 1H), 7.81 (m,1H), 7.55 (dd, J=7.5, 1.8, 1H), 7.49-7.44 (m, 1H), 7.42-7.33 (m, 3H),7.30 (dd, J=12.6, 1.7, 1H), 7.21 (dd, J=8.0, 1.2, 1H), 5.39 (s, 1H),2.25 (s, 3H).

Example 624

5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-6-(trifluoromethyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₄F₄N₄O, 426.11; m/z found, 427.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 2H), 8.04 (m, 1H), 7.59-7.48 (m,4H), 7.41 (m, 1H), 7.35-7.24 (m, 4H), 6.89 (s, 2H).

Example 625

5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)-6-(trifluoromethyl)pyridine. MS(ESI): mass calcd. for C₂₂H₁₄F₄N₄O, 426.11; m/z found, 427.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.33-8.27 (m, 1H), 8.05-7.98 (m, 2H), 7.81 (m,1H), 7.62-7.56 (m, 1H), 7.54-7.47 (m, 2H), 7.44-7.38 (m, 1H), 7.35-7.23(m, 4H), 6.70 (s, 2H).

Example 626

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)nicotinonitrile. MS (ESI): masscalcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.57 (dd, J=2.3, 0.8, 1H), 8.34-8.31 (m, 1H), 8.24 (dd,J=8.8, 2.3, 1H), 7.99 (d, J=1.4, 1H), 7.83 (m, 1H), 7.60 (dd, J=7.6,1.6, 1H), 7.53-7.47 (m, 1H), 7.45-7.40 (m, 1H), 7.35-7.28 (m, 3H), 7.19(dd, J=8.6, 0.6, 1H), 6.70 (s, 2H).

Example 627

6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 6-(2-bromophenoxy)nicotinonitrile and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₁₄FN₅O, 383.12; m/z found, 384.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (dd, J=2.3, 0.8, 1H), 8.44 (d, J=1.6,2H), 8.26 (dd, J=8.6, 2.3, 1H), 7.59 (dd, J=7.6, 1.8, 1H), 7.56-7.48 (m,2H), 7.45-7.39 (m, 1H), 7.36-7.27 (m, 3H), 7.21 (dd, J=8.7, 0.7, 1H),6.89 (s, 2H).

Example 628

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)ethanol. MS (ESI): mass calcd. forC₁₈H₁₆FN₃O₂, 325.12; m/z found, 326.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.35 (s, 1H), 8.00 (d, J=1.2, 1H), 7.86 (m, 1H), 7.55-7.45 (m, 2H),7.40-7.36 (m, 1H), 7.35-7.29 (m, 1H), 7.11 (d, J=8.2, 1H), 7.02 (m, 1H),6.66 (s, 2H), 4.81 (s, 1H), 4.04 (t, J=5.0, 2H), 3.73-3.63 (m, 2H).

Example 629

2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)ethanoland5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₆FN₃O₂, 325.12; m/z found, 326.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=1.0, 2H), 7.57-7.51 (m, 2H),7.48-7.44 (m, 1H), 7.38-7.30 (m, 2H), 7.12 (d, J=8.4, 1H), 7.02 (m, 1H),6.90 (s, 2H), 4.05 (t, J=5.0, 2H), 3.68 (t, J=5.0, 2H).

Example 630

5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)piperidine. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.36 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.89 (m, 1H), 7.46-7.31 (m,4H), 7.19 (d, J=8.2, 1H), 7.05 (m, 1H), 6.68 (s, 2H), 4.68-4.59 (m, 1H),2.97-2.87 (m, 4H), 2.07-1.93 (m, 2H), 1.82-1.54 (m, 2H).

Example 631

5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)piperidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 2H), 8.29 (s, 1H), 7.56 (m, 1H),7.46-7.31 (m, 4H), 7.20 (d, J=8.4, 1H), 7.05 (m, 1H), 6.86 (s, 2H),4.62-4.66 (m, 1H), 2.91-2.93 (m, 4H), 2.07-1.96 (m, 2H), 1.77-1.65 (m,2H).

Example 632

5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (R)-3-(2-bromophenoxy)piperidine. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.38 (dd, J=2.1, 1.6, 1H), 8.08 (d, J=1.5, 1H), 7.94-7.90 (m,1H), 7.48-7.37 (m, 4H), 7.23-7.13 (m, 2H), 4.52-4.40 (m, 1H), 3.30-3.24(m, 2H), 3.20-3.06 (m, 2H), 2.01-1.69 (m, 4H).

Example 633

5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (R)-3-(2-bromophenoxy)piperidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.48-8.45 (m, 2H), 7.60-7.48 (m, 2H),7.46-7.34 (m, 3H), 7.23 (d, J=8.0, 1H), 7.13-7.06 (m, 1H), 6.87 (s, 2H),4.68-4.56 (m, 1H), 3.35-3.30 (m, 1H), 3.11-2.99 (m, 2H), 2.98-2.89 (m,1H), 2.03-1.93 (m, 1H), 1.88-1.77 (m, 1H), 1.72-1.58 (m, 2H).

Example 634

5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (S)-3-(2-bromophenoxy)piperidine. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.37 (s, 1H), 8.02 (s, 1H), 7.91-7.87 (m, 1H), 7.52-7.45 (m,2H), 7.42 (d, J=7.4, 1H), 7.36 (d, J=7.1, 1H), 7.22 (d, J=8.3, 1H),7.12-7.08 (m, 1H), 6.69 (s, 2H), 4.57 (br m, 1H), 3.09-3.04 (m, 3H),2.98-2.92 (m, 1H), 2.02-1.90 (m, 1H), 1.87-1.75 (m, 1H), 1.70-1.58 (m,2H).

Example 635

5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using (S)-3-(2-bromophenoxy)piperidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₁FN₄O, 364.17; m/z found, 365.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 2H), 7.59-7.48 (m, 2H), 7.44 (d,J=8.1, 1H), 7.40-7.35 (m, 2H), 7.24 (d, J=8.3, 1H), 7.11-7.07 (m, 1H),6.87 (s, 2H), 4.73-4.53 (m, 1H), 3.38-3.30 (m, 1H), 3.12-2.86 (m, 3H),2.04-1.94 (m, 1H), 1.80-1.71 (m, 2H), 1.65-1.54 (m, 1H).

Example 636

5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-6-cyclopropylpyrimidine. MS (ESI):mass calcd. for C₂₃H₁₈FN₅O, 399.15; m/z found, 399.9 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.30 (s, 1H), 7.97 (s, 1H), 7.81 (m, 1H),7.58-7.54 (m, 1H), 7.49-7.43 (m, 1H), 7.41-7.35 (m, 1H), 7.33-7.23 (m,3H), 6.98 (s, 1H), 6.68 (s, 2H), 2.09-2.01 (m, 1H), 1.02-0.89 (m, 4H).

Example 637

5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)-6-cyclopropylpyrimidine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₃H₁₈FN₅O, 399.15; m/z found, 399.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.42 (s, 2H), 7.56-7.50 (m,2H), 7.48-7.43 (m, 1H), 7.41-7.36 (m, 1H), 7.33-7.23 (m, 3H), 6.99 (s,1H), 6.86 (s, 2H), 2.09-2.01 (m, 1H), 1.02-0.92 (m, 4H).

Example 638

5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)pyridin-2-amine. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.36-8.30 (m, 1H), 7.99 (d, J=1.4, 1H), 7.90-7.82 (m, 1H),7.76 (d, J=6.5, 1H), 7.63 (dd, J=7.7, 1.7, 1H), 7.57-7.48 (m, 1H),7.46-7.40 (m, 1H), 7.39-7.31 (m, 2H), 7.27 (d, J=8.0, 1H), 6.70 (s, 2H),6.55 (s, 2H), 6.23 (dd, J=6.4, 2.2, 1H), 5.86 (d, J=2.3, 1H).

Example 639

5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-(2-bromophenoxy)pyridin-2-amine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 2H), 7.77 (d, J=6.3, 1H), 7.65-7.48(m, 3H), 7.45-7.32 (m, 3H), 7.25 (d, J=8.0, 1H), 6.88 (s, 2H), 6.52 (s,2H), 6.23 (dd, J=6.3, 2.2, 1H), 5.87 (d, J=2.2, 1H).

Example 640

5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)ethanamine. MS (ESI): mass calcd. forC₁₈H₁₇FN₄O, 324.14; m/z found, 325.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.36 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=1.3, 1H), 7.90-7.86 (m, 1H),7.50-7.45 (m, 2H), 7.41-7.33 (m, 2H), 7.14 (d, J=8.1, 1H), 7.08-7.05 (m,1H), 6.67 (s, 2H), 4.10 (t, J=5.4, 2H), 3.01 (t, J=5.4, 2H).

Example 641

5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)ethanamine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₇FN₄O, 324.14; m/z found, 325.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=0.9, 2H), 8.29 (s, 1H), 7.58-7.54(m, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, J=8.0, 1.4, 1H), 7.39-7.34 (m,2H), 7.15 (d, J=8.1, 1H), 7.09-7.05 (m, 1H), 6.86 (s, 2H), 4.13 (t,J=5.4, 2H), 3.05 (t, J=5.4, 2H).

Example 642

{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)acetonitrile. MS (ESI): mass calcd.for C₁₈H₁₃FN₄O, 320.11; m/z found, 320.9 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.40-8.33 (m, 1H), 8.01 (d, J=1.4, 1H), 7.91-7.87 (m, 1H),7.45-7.39 (m, 3H), 7.37 (s, 1H), 7.30-7.24 (m, 1H), 7.18-7.15 (m, 1H),6.68 (s, 2H), 5.18 (s, 2H).

Example 643

{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)acetonitrile and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₃FN₄O, 320.11; m/z found, 320.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.5, 2H), 7.60-7.56 (m, 1H),7.46-7.34 (m, 4H), 7.26 (d, J=8.0, 1H), 7.18-7.14 (m, 1H), 6.87 (s, 2H),5.18 (s, 2H).

Example 644

{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid

The title compound was prepared in a manner similar to that described inExample 88 using 2-(2-bromophenoxy)acetic acid and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₄FN₃O₃, 339.10; m/z found, 339.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=1.4, 2H), 7.71 (d, J=13.3, 1H),7.51 (d, J=5.7, 2H), 7.29 (dd, J=7.5, 1.7, 1H), 7.25-7.17 (m, 1H),6.92-6.89 (m, 1H), 6.88-6.80 (m, 3H), 4.14 (s, 2H).

3-Bromo-2-(piperidin-4-yloxy)pyridine Step A: tert-Butyl4-((3-bromopyridin-2-yl)oxy)piperidine-1-carboxylate

A suspension of 2-bromophenol (2.0 g, 10 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (2.09 g, 10.4 mmol), and cesiumcarbonate (6.8 g, 21 mmol) in dimethylsulfoxide (10 mL) was heated at130° Celsius overnight. The reaction mixture was then cooled to rt,diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL).The combined organic extracts were washed with water (3×10 mL) and driedover anhydrous magnesium sulfate. The solvent was removed in vacuo, andthe residue purified by FCC to provide the title compound.

Step B: 3-Bromo-2-(piperidin-4-yloxy)pyridine

To a solution of tert-butyl4-((3-bromopyridin-2-yl)oxy)piperidine-1-carboxylate in MeOH (10 mL) wasadded HCl (2 mL, 1 N). The reaction mixture was stirred at rt for 2 hbefore adjusting the pH to ˜9 with NH₄OH. The mixture was thenconcentrated to dryness and the crude product purified by FCC to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (dd, J=4.8, 1.7,1H), 8.06 (dd, J=7.7, 1.7, 1H), 6.98 (dd, J=7.7, 4.9, 1H), 5.31 (m, 1H),3.18-3.07 (m, 4H), 2.22-2.05 (m, 2H), 1.92 (m, 2H).

4-((3-Bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide Step A:3-Bromo-2-((tetrahydro-2H-thiopyran-4-yl)oxy)pyridine

To a 100 mL reaction tube, equipped with a reflux condenser and under anitrogen atmosphere, was added a solution consisting oftetrahydro-2H-thiopyran-4-ol (1.04 g, 8.78 mmol) in DMF (2 mL). Themixture was cooled to the 0° Celsius, and then treated with NaH (0.540g, 60% dispersion in mineral oil, 13.5 mmol). When the addition wascomplete, the reaction was warmed to rt and stirred 30 min before adding3-bromo-2-chloropyridine (1.3 g, 6.8 mmol), and heating at 130° Celsiusfor 10 hours. The reaction mixture was cooled to rt and carefullyquenched with H₂O, concentrated to remove the solvent, and extractedwith water (20 mL) and EtOAc (3×20 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated to dryness. The crudematerial was purified by FCC to provide the title compound.

Step B: 4-((3-Bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide

To a 100 mL round-bottomed flask, was added a solution, consisting of3-bromo-2-(tetrahydro-2H-thiopyran-4-yloxy)pyridine (1.6 g, 5.8 mmol)and DCM (25 mL), under a nitrogen atmosphere. The mixture was cooled tothe 0° Celsius and m-CPBA (3.63 g, 14.6 mmol, 77%) was added inportions. When the addition was complete, the reaction was warmed to rtand stirred for 3 h. The reaction was quenched by adding H₂O (10 mL) andthe organic layer isolated. The aqueous phase was extracted with DCM(3×20 mL) and the combined organic extracts were washed with saturatedNaHCO₃, dried over sodium sulfate, filtered, and concentrated todryness. The crude product was purified by FCC to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (dd, J=4.9, 1.6, 1H), 8.07(dd, J=7.8, 1.6, 1H), 6.99 (dd, J=7.7, 4.9, 1H), 5.43-5.36 (m, 1H),3.23-3.19 (m, 2H), 3.15 (dd, J=14.3, 7.3, 2H), 2.31-2.25 (m, 4H).

2-((3-Bromopyridin-2-yl)oxy)ethanol

Sodium hydride (1.6 g, 42 mmol) was added to cooled (ice-water bath)ethane-1,2-diol (5 mL) and the resulting mixture stirred at rt for 30min before adding 3-bromo-2-chloropyridine (2.0 g, 100 mmol). Themixture was then heated at 130° Celsius under a N₂ atmosphere overnightbefore cooling to rt and subjecting the reaction mixture to FCCpurification to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ8.05 (dd, J=4.9, 1.7, 1H), 7.82 (dd, J=7.6, 1.7, 1H), 6.80 (dd, J=7.6,4.9, 1H), 4.54-4.50 (m, 2H), 3.97 (dd, J=8.8, 5.5, 2H), 3.18 (t, J=5.8,1H).

trans-4-((3-Bromopyridin-2-yl)oxy)cyclohexanamine

To a cooled (0° C.) 150 mL reaction tube equipped with reflux condenserand under a nitrogen atmosphere, were added trans-4-aminocyclohexanol(2.0 g, 17 mmol), NaH (2.08 g, 60% dispersion in mineral oil, 52.1mmol), and DMF (25 mL) to give a colorless solution. After stirring for1 h, 3-bromo-2-chloropyridine (3.34 g, 17.4 mmol) was added to themixture And the resulting mixture heated at 60° Celsius for 5 h. Afterthe starting material was consumed, the reaction was cooled to roomtemperature and quenched with H₂O (2 mL). The reaction mixture wasconcentrated to dryness and the resultant residue purified by FCC toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (dd, J=4.8,1.6, 1H), 7.98 (dd, J=7.7, 1.6, 1H), 6.89 (dd, J=7.7, 4.8, 1H), 4.92(dd, J=9.4, 5.2, 1H), 2.98 (s, 1H), 2.05 (m, 2H), 1.95 (m, 2H),1.53-1.38 (m, 4H)

3-Bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine

The title compound was prepared in a manner similar to that described inStep A for the synthesis of4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran 1,1-dioxide usingtetrahydro-2H-pyran-4-ol. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (dd, J=4.8,1.7, 1H), 7.99 (dd, J=7.7, 1.7, 1H), 6.90 (dd, J=7.7, 4.8, 1H), 5.22 (m,1H), 3.86-3.77 (m, 2H), 3.49 (m, 2H), 1.95 (m, 2H), 1.61 (m, 2H).

(R)-2-((3-Bromopyridin-2-yl)oxy)propan-1-ol Step A:(R)-2-((1-(Benzyloxy)propan-2-yl)oxy)-3-bromopyridine

To a stirred solution of (R)-1-(benzyloxy)propan-2-ol (2.0 g, 12 mmol)in dry DMF (5 mL) was added NaH (1.5 g, 36 mmol) at 0 Celsius. Thereaction mixture was then stirred for 30 min before adding3-bromo-2-chloropyridine (2.3 g, 12 mmol) and stirring continued foranother 4 h. The reaction was quenched by slow addition of water (10 mL)and the resultant mixture extracted with ethyl acetate (3×10 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, concentratedto dryness, and the crude product purified by FCC to provide the titlecompound.

Step B: (R)-2-((3-Bromopyridin-2-yl)oxy)propan-1-ol

To a stirred solution of(R)-2-((1-(benzyloxy)propan-2-yl)oxy)-3-bromopyridine (2.4 g, 7.5 mmol)in dry DCM (10 mL) was added BBr₃ (7.5 mL, 22 mmol, 3 M in DCM) at −78Celsius in a drop-wise manner and stirring continued for 3 h. Thereaction mixture was warmed to rt and the pH adjusted to −7-8 with sat.NaHCO₃ (30 mL). The mixture was extracted with DCM (2×10 mL), and thecombined extracts dried over Na₂SO₄, filtered, concentrated to dryness.The crude product was purified by FCC to provide the title compound. ¹HNMR (400 MHz, CDCl₃) δ 8.05-7.99 (m, 1H), 7.84-7.75 (m, 1H), 6.83-6.71(m, 1H), 5.25-5.12 (m, 1H), 3.78 (d, J=5.1, 2H), 3.29 (s, 1H), 1.37 (d,J=6.4, 3H).

(S)-2-((3-Bromopyridin-2-yl)oxy)propan-1-ol

The title compound was prepared in a manner similar to that describedfor (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol using(S)-1-(benzyloxy)propan-2-ol. ¹H NMR (400 MHz, CDCl₃) δ 8.07-7.97 (m,1H), 7.79 (m, 1H), 6.76 (m, 1H), 5.26-5.12 (m, 1H), 3.77 (t, J=6.1, 2H),3.35 (s, 1H), 1.36 (d, J=6.3, 3H).

Example 645

5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 3-bromo-2-(piperidin-4-yloxy)pyridine. MS (ESI): masscalcd. for C₂₀H₂₀FN₅O, 365.17; m/z found, 366.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.40 (dd, J=2.3, 1.5, 1H), 8.20 (dd, J=4.9, 1.9, 1H), 8.04(d, J=1.5, 1H), 8.00-7.88 (m, 2H), 7.60-7.52 (m, 2H), 7.15 (dd, J=7.4,4.9, 1H), 6.73 (s, 2H), 5.45-5.32 (m, 1H), 3.11 (t, J=5.9, 4H),2.23-2.06 (m, 2H), 2.04-1.83 (m, 2H).

Example 646

5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 3-bromo-2-(piperidin-4-yloxy)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₂₀FN₅O, 365.17; m/z found, 366.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=1.5, 2H), 8.20 (dd, J=4.9, 1.9,1H), 7.89 (dd, J=7.4, 1.9, 1H), 7.68-7.51 (m, 3H), 7.14 (dd, J=7.4, 4.9,1H), 6.90 (s, 2H), 5.36 (s, 1H), 3.06 (d, J=11.3, 4H), 2.13 (s, 2H),1.86 (s, 2H).

Example 647

5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran1,1-dioxide. MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found,415.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.21 (dd, J=4.8,1.6, 1H), 8.04 (s, 1H), 7.99-7.88 (m, 2H), 7.61-7.51 (m, 2H), 7.16 (dd,J=7.4, 5.0, 1H), 6.71 (s, 2H), 5.49-5.38 (m, 1H), 3.21-3.15 (m, 2H),3.10-2.99 (m, 2H), 2.30 (d, J=5.1, 4H).

Example 648

5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 4-((3-bromopyridin-2-yl)oxy)tetrahydro-2H-thiopyran1,1-dioxide and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=1.3, 2H), 8.21 (dd, J=4.9, 1.8,1H), 7.90 (dd, J=7.4, 1.8, 1H), 7.64 (m, 1H), 7.58 (dd, J=12.4, 1.5,1H), 7.53 (dd, J=8.0, 1.7, 1H), 7.16 (dd, J=7.4, 4.9, 1H), 6.89 (s, 2H),5.42 (dd, J=6.3, 3.0, 1H), 3.21 (dd, J=14.5, 8.0, 2H), 3.09-3.01 (m,2H), 2.34-2.24 (m, 4H).

Example 649

2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol

The title compound was prepared in a manner similar to that described inExample 88 using 2-((3-bromopyridin-2-yl)oxy)ethanol and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₇H₁₅FN₄O₂, 326.12; m/z found, 326.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.3, 2H), 8.15 (dd, J=4.9, 1.8,1H), 7.84 (dd, J=7.4, 1.8, 1H), 7.65-7.52 (m, 3H), 7.08 (dd, J=7.4, 5.0,1H), 6.87 (s, 2H), 4.80 (s, 1H), 4.40-4.32 (m, 2H), 3.70 (t, J=5.0, 2H).

Example 650

2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol

The title compound was prepared in a manner similar to that described inExample 88 using 2-((3-bromopyridin-2-yl)oxy)ethanol. MS (ESI): masscalcd. for C₁₇H₁₅FN₄O₂, 326.12; m/z found, 327.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.36 (d, J=1.6, 1H), 8.15 (dd, J=4.9, 1.8, 1H), 8.00 (d,J=1.4, 1H), 7.93-7.83 (m, 2H), 7.58 (m, 2H), 7.08 (dd, J=7.4, 4.9, 1H),6.68 (s, 2H), 4.80 (s, 1H), 4.39-4.34 (m, 2H), 3.70 (d, J=4.5, 2H).

Example 651

5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using trans-4-((3-bromopyridin-2-yl)oxy)cyclohexanamine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.1, 2H), 8.15 (dd, J=4.9, 1.7,1H), 7.81 (dd, J=7.4, 1.7, 1H), 7.53 (m, 3H), 7.05 (dd, J=7.4, 5.0, 1H),6.87 (s, 2H), 5.02 (m, 1H), 2.63 (m, 1H), 2.05 (m, 2H), 1.77 (m, 2H),1.39 (m, 2H), 1.18 (m, 4H).

Example 652

5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amineformic acid salt

The title compound was prepared in a manner similar to that described inExample 88 using trans-4-((3-bromopyridin-2-yl)oxy)cyclohexanamine. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) 8.42 (s, 1H), 8.36 (d, J=1.9, 1H), 8.15 (dd,J=4.9, 1.8, 1H), 8.00 (d, J=1.4, 1H), 7.88 (m, 1H), 7.83 (dd, J=7.4,1.9, 1H), 7.53-7.49 (m, 1H), 7.48 (s, 1H), 7.06 (dd, J=7.4, 4.9, 1H),6.70 (s, 2H), 5.02 (m, 1H), 2.89 (s, 1H), 2.10 (m, 2H), 1.89 (m, 2H),1.45-1.33 (m, 4H).

Example 653

5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 367.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.38-8.31 (m, 1H), 8.15 (dd, J=4.9, 1.9, 1H),8.00 (d, J=1.5, 1H), 7.94-7.83 (m, 2H), 7.57-7.48 (m, 2H), 7.07 (dd,J=7.4, 4.9, 1H), 6.68 (s, 2H), 5.38-5.23 (m, 1H), 3.83-3.68 (m, 2H),3.50 (m, 2H), 1.98 (d, J=7.5, 2H), 1.71-1.54 (m, 2H).

Example 654

5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 88 using 3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 367.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.5, 2H), 8.15 (dd, J=4.9, 1.9,1H), 7.84 (dd, J=7.4, 1.9, 1H), 7.64-7.48 (m, 3H), 7.07 (dd, J=7.4, 4.9,1H), 6.86 (s, 2H), 5.30 (m, 1H), 3.81-3.72 (m, 2H), 3.49 (m, 2H), 1.98(m, 2H), 1.70-1.55 (m, 2H).

Example 655

(2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol. MS (ESI):mass calcd. for C₁₈H₁₇FN₄O₂, 340.13; m/z found, 341.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.41-8.35 (m, 1H), 8.17 (dd, J=4.9, 1.8, 1H), 8.03(d, J=1.4, 1H), 7.94-7.84 (m, 2H), 7.66-7.55 (m, 2H), 7.09 (dd, J=7.4,4.9, 1H), 6.71 (s, 2H), 5.35-5.23 (m, 1H), 4.86 (t, J=5.4, 1H),3.62-3.51 (m, 2H), 1.25 (d, J=6.3, 3H).

Example 656

(2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol

The title compound was prepared in a manner similar to that described inExample 88 using (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₇FN₄O₂, 340.13; m/z found, 340.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=1.4, 2H), 8.17 (dd, J=4.9, 1.9,1H), 7.85 (dd, J=7.4, 1.9, 1H), 7.67-7.54 (m, 3H), 7.09 (dd, J=7.4, 4.9,1H), 6.89 (s, 2H), 5.35-5.23 (m, 1H), 4.86 (t, J=5.4, 1H), 3.62-3.51 (m,2H), 1.25 (d, J=6.3, 3H).

Example 657

(2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol. MS (ESI):mass calcd. for C₁₈H₁₇FN₄O₂, 340.13; m/z found, 341.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.38-8.32 (m, 1H), 8.14 (dd, J=4.9, 1.9, 1H), 8.00(d, J=1.5, 1H), 7.91-7.80 (m, 2H), 7.64-7.52 (m, 2H), 7.05 (dd, J=7.4,4.9, 1H), 6.68 (s, 2H), 5.32-5.22 (m, 1H), 4.82 (t, J=5.3, 1H),3.58-3.48 (m, 2H), 1.22 (d, J=6.3, 3H).

Example 658

(2I)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol

The title compound was prepared in a manner similar to that described inExample 88 using (S)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₈H₁₇FN₄O₂, 340.13; m/z found, 341.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.2, 2H), 8.14 (dd, J=4.9, 1.8,1H), 7.82 (dd, J=7.4, 1.8, 1H), 7.64-7.52 (m, 3H), 7.05 (dd, J=7.4, 4.9,1H), 6.86 (s, 2H), 5.34-5.21 (m, 1H), 4.83 (s, 1H), 3.58-3.47 (m, 2H),1.22 (d, J=6.3, 3H).

Example 659

N-(4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanesulfonamide

The title compound was prepared in a manner similar to that described inExample 341 using (2-(methylsulfonamido)phenyl)boronic acid in Step B.MS (CI): mass calcd. for C₁₈H₁₆FN₃O₂S, 357.09; m/z found, 358.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 14.69-13.78 (m, 1H), 9.21-9.14 (s, 1H),8.52-8.10 (m, 5H), 7.72-7.63 (m, 1H), 7.52-7.36 (m, 10H), 7.18-7.10 (d,J=9.3, 1H), 2.90-2.80 (s, 3H).

Example 660

5-(3-Fluoro-2′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine

The title compound was prepared in a manner similar to that described inExample 341 using (2-(morpholinosulfonyl)phenyl)boronic acid in Step B.MS (CI): mass calcd. for C₂₁H₂₀FN₃O₃S, 413.12; m/z found, 414.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.20-8.13 (s, 1H), 8.05-7.98 (m, 1H),7.81-7.73 (m, 1H), 7.70-7.60 (m, 3H), 7.57-7.50 (m, 1H), 7.49-7.45 (dd,J=7.6, 1.2, 1H), 7.36-7.29 (dd, J=12.0, 1.6, 1H), 7.29-7.24 (m, 1H),6.59-6.52 (d, J=8.5, 1H), 6.26-6.14 (s, 2H), 3.44-3.36 (m, 5H),2.82-2.72 (m, 5H).

Example 661

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 341 using (2-(N-methylsulfamoyl)phenyl)boronic acid in Step B.MS (CI): mass calcd. for C₁₈H₁₆FN₃O₂S, 357.09; m/z found, 358.0 [M+H]⁺.¹H NMR (500 MHz, acetone-d₆) δ 8.29-8.20 (s, 1H), 7.73-7.28 (m, 9H),6.72-6.65 (m, 1H), 5.74-5.53 (d, J=8.2, 2H), 3.01-2.93 (s, 3H).

Example 662

4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetate

A mixture of4′-(6-aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide(55 mg, 0.14 mmol) and TFA (1 mL) was heated to 50° Celsius for 1.5 h.

The mixture was cooled to rt and diluted with ether (10 mL. Theresulting precipitate was collected via filtration and dried to providethe title compound. MS (CI): mass calcd. for C₁₇H₁₄FN₃O₂S, 343.08; m/zfound, 344.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.29-7.90 (m, 4H),7.70-7.58 (m, 4H), 7.46-7.30 (m, 6H), 7.14-7.04 (d, J=9.2, 1H).

Example 663

5-(2′-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine

The title compound was prepared in a manner similar to that described inExample 347 using(1S,4S)-5-((2-bromophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.1]heptane. MS(CI): mass calcd. for C₂₁H₁₉FN₄O₃S, 426.12; m/z found, 427.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.20-8.13 (s, 1H), 8.05-7.98 (m, 1H), 7.81-7.73(m, 1H), 7.70-7.60 (m, 3H), 7.57-7.50 (m, 1H), 7.49-7.45 (dd, J=7.6,1.2, 1H), 7.36-7.29 (dd, J=12.0, 1.6, 1H), 7.29-7.24 (m, 1H), 6.59-6.52(d, J=8.5, 1H), 6.26-6.14 (s, 2H), 3.44-3.36 (m, 5H), 2.82-2.72 (m, 5H).

Example 664

4′-(6-Aminopyrazin-2-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using2-bromo-N-((3-hydroxyazetidin-3-yl)methyl)benzenesulfonamide. MS (CI):mass calcd. for C₂₀H₂₀FN₅O₃S, 429.13; m/z found, 430.0 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.79-8.64 (s, 1H), 8.63-8.51 (s, 1H), 8.43-8.37 (m,1H), 8.06-8.02 (d, J=1.5, 1H), 8.00-7.94 (m, 1H), 7.94-7.87 (m, 1H),7.84-7.77 (m, 1H), 7.75-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.49-7.43 (m,1H), 7.36-7.27 (m, 2H), 6.89-6.55 (s, 2H), 6.36-6.08 (s, 1H), 3.93-3.88(m, 2H), 3.72-3.70 (m, 2H), 3.04-2.97 (d, J=6.5, 2H).

Example 665

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide. MS (CI):mass calcd. for C₂₁H₂₂FN₃O₃S, 415.14; m/z found, 418.0 (off) [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.30-7.97 (m, 5H), 7.71-7.57 (m, 3H), 7.42-7.29(m, 3H), 7.12-7.06 (d, J=9.2, 1H), 6.70-6.63 (s, 1H), 3.20-3.13 (s, 2H),1.00-0.92 (s, 6H).

Example 666

4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 347 using2-bromo-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylbenzenesulfonamide.MS (CI): mass calcd. for C₂₁H₂₂FN₃O₃S, 494.17; m/z found, 494.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.27-8.21 (d, J=9.5, 1H), 8.17-8.10 (m, 2H),7.72-7.65 (m, 1H), 7.65-7.54 (m, 2H), 7.41-7.34 (m, 3H), 7.33-7.24 (m,5H), 7.19-7.12 (d, J=9.3, 1H), 4.57-4.49 (d, J=8.4, 1H), 3.97-3.86 (m,1H), 2.63-2.52 (s, 3H), 0.94-0.61 (d, J=6.9, 3H).

Example 667

4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamideStep A: (4-(6-Amino-5-fluoropyridin-3-vyl)-3-fluorophenyl)boronic acid

A mixture of 4-chloro-2-fluorophenylboronic acid (820 mg, 4.70 mmol),2-amino-3-fluoro-5-bromopyrazine (900 mg, 4.70 mmol), palladiumtrifluoroacetate (31 mg, 0.094 mmol), triphenylphosphine (49 mg, 0.19mmol), toluene (15 mL), EtOH (15 mL), and Na₂CO₃ (9 mL, 2 M) wasdeoxygenated by sparging with nitrogen. The mixture was then heated at50° Celsius while stirring for 16 h. The mixture was then cooled to rtand diluted with EtOAc. The mixture was filtered and the filtratetransferred to a separatory funnel. The organic phase was isolated, andthe aqueous phase extracted with EtOAc.

The combined organic extracts were washed with brine, dried over Na₂SO₄,concentrated to dryness, and subjected to FCC to give5-(4-chloro-2-fluorophenyl)-3-fluoropyridin-2-amine (980 mg). Thismaterial was combined with bis(pinacolato)diboron (1.03 g, 4.94 mmol)andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)(62 mg, 0.079 mmol) and anhydrous potassium acetate (1.06 g, 11.8 mmol)in a sealable vessel under nitrogen. Deoxygenated 1,4-dioxane (150 mL)was added, and the reaction vessel sealed and heated at 60° Celsius for16 h. The mixture was cooled to rt, diluted with EtOAc, and filteredthrough a pad of silica gel, and concentrated to give a brown residue.This material was taken up in HCl (40 mL, 1 M) and MeOH (ca. 5 mL), andany insoluble material was removed by filtration. The resulting solutionwas treated with solid NaHCO₃ to achieve pH 7. The precipitate wascollected and dried to give4-(6-amino-5-fluoropyridin-3-yl)-3-fluorophenyl)boronic acid (968 mg,84%). MS (CI): mass calcd. for C₁₁H₉BF₂N₂O₂, 250.01; m/z found, 252.0[M+H]⁺.

Step B:4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,trifluoroacetate salt

A mixture of 4-(6-amino-5-fluoropyridin-3-yl)-3-fluorophenyl)boronicacid (80 mg, 0.32 mmol),2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide (118 mg,0.380 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (12 mg, 0.016 mmol), K₂CO₃ (0.80 mL, 1.6mmol, 2 M), and 1,4-dioxane (2 mL) was deoxygenated by sparging withnitrogen for 10 min, then heated at 80° Celsius for 16 h. The mixturewas filtered using a syringe filter and directly subjected to HPLCpurification to provide the title compound (74 mg, 42%). MS (CI): masscalcd. for C₂₁H₂₁F₂N₃O₃S, 433.13; m/z found, 435.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.13-8.04 (m, 2H), 7.80-7.73 (d, J=12.3, 1H), 7.69-7.64(m, 1H), 7.64-7.56 (m, 2H), 7.40-7.36 (m, 1H), 7.36-7.31 (m, 1H),7.31-7.26 (m, 1H), 6.62-6.55 (s, 1H), 3.19-3.11 (s, 2H), 1.01-0.87 (s,6H).

Example 668

(racemic)-1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-ol

The title compound was prepared in a manner similar to that described inExample 676 using (racemic)-1-((2-bromophenyl)sulfonyl)piperidin-3-ol inStep B. MS (CI): mass calcd. for C₂₂H₂₁F₂N₃O₃S, 445.13; m/z found, 448.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.11-8.06 (m, 1H), 8.06-7.98 (m, 2H),7.74-7.68 (m, 1H), 7.66-7.55 (m, 2H), 7.44-7.39 (m, 1H), 7.36-7.29 (m,2H), 3.45-3.36 (m, 1H), 1.71-1.62 (m, 1H), 3.30-3.23 (m, 1H), 3.17-3.09(d, J=12.7, 1H), 2.52-2.42 (m, 1H), 2.30-2.21 (dd, J=12.0, 9.1, 1H),1.91-1.81 (m, 1H), 1.43-1.31 (m, 1H), 1.28-1.17 (m, 1H).

Example 669

4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared in a manner similar to that described inExample 676 using2-bromo-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylbenzenesulfonamidein Step B. MS (CI): mass calcd. for C₂₇H₂₅F₂N₃O₃S, 509.16; m/z found,510.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.15-8.09 (m, 1H), 8.04-7.95 (m,2H), 7.69-7.63 (m, 1H), 7.62-7.52 (m, 2H), 7.38-7.22 (m, 8H), 4.55-4.45(d, J=8.4, 1H), 3.95-3.81 (m, 1H), 2.59-2.49 (s, 3H), 0.79-0.70 (d,J=6.9, 3H).

Example 670

N-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)acetamide

The title compound was prepared in a manner similar to that described inExample 676 using N-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)acetamidein Step B. MS (CI): mass calcd. for C₂₄H₂₄F₂N₄O₃S, 486.15; m/z found,487.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.11-8.01 (m, 3H), 7.74-7.67 (m,1H), 7.65-7.57 (m, 2H), 7.43-7.38 (m, 1H), 7.36-7.28 (m, 2H), 3.68-3.57(m, 1H), 3.38-3.32 (d, J=13.1, 2H), 2.58-2.48 (m, 2H), 1.90-1.86 (s,3H), 1.78-1.69 (m, 2H), 1.38-1.25 (m, 2H).

Example 671

2-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)ethanol

The title compound was prepared in a manner similar to that described inExample 676 using 2-(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)ethanolin Step B. MS (CI): mass calcd. for C₂₄H₂₅F₂N₃O₃S, 473.16; m/z found,474.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.12-7.99 (m, 3H), 7.73-7.67 (m,1H), 7.65-7.55 (m, 2H), 7.43-7.38 (m, 1H), 7.38-7.30 (m, 2H), 3.51-3.45(m, 2H), 3.28-3.21 (m, 2H), 2.48-2.40 (m, 1H), 2.18-2.10 (m, 1H),1.78-1.69 (m, 1H), 1.65-1.55 (m, 1H), 1.54-1.43 (m, 1H), 1.42-1.27 (m,3H), 1.04-0.89 (m, 1H).

Example 672

(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)methanol

The title compound was prepared in a manner similar to that described inExample 676 using 2-(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)methanolin Step B. MS (CI): mass calcd. for C₂₃H₂₃F₂N₃O₃S, 459.14; m/z found,460.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.11-8.00 (m, 3H), 7.73-7.68 (m,1H), 7.66-7.55 (m, 2H), 7.45-7.30 (m, 3H), 3.45-3.39 (m, 1H), 3.38-3.34(dd, J=11.0, 5.2, 1H), 3.29-3.24 (d, J=11.7, 1H), 3.24-3.18 (dd, J=11.0,7.7, 1H), 2.47-2.38 (m, 1H), 2.23-2.14 (m, 1H), 1.68-1.56 (m, 2H),1.55-1.43 (m, 1H), 1.39-1.26 (m, 1H), 1.04-0.92 (m, 1H).

Example 673

2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using(6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and(R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd.for C₁₈H₁₈FN₅O₃S, 403.11; m/z found, 404.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 9.02 (d, J=0.8, 2H), 8.52-8.47 (m, 1H), 8.09 (dd, J=7.9, 1.4,1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.46 (dd,J=7.5, 1.4, 1H), 3.74-3.59 (m, 1H), 2.84-2.66 (m, 2H), 1.06 (d, J=6.3,3H).

Example 674

2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using(6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): masscalcd. for C₁₈H₁₅F₄N₅O₂S, 441.09; m/z found, 442.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.94 (d, J=1.1, 2H), 8.51-8.46 (m, 1H), 8.37-8.31 (m, 1H),8.03 (dd, J=8.1, 1.9, 1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.68 (d, J=7.9,1H), 2.86 (q, J=7.3, 2H), 1.02 (t, J=7.2, 3H).

Example 675

2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and5-(5-chloro-3-fluoropyridin-2-yl)pyrimidin-2-amine. MS (ESI): masscalcd. for C₁₉H₂₀FN₅O₂S, 401.13; m/z found, 402.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.97 (d, J=1.1, 2H), 8.50-8.44 (m, 1H), 8.17 (dd, J=8.0,1.3, 1H), 7.79 (dd, J=12.0, 1.8, 1H), 7.70 (m, 1H), 7.63 (m, 1H), 7.43(dd, J=7.5, 1.5, 1H), 1.09 (s, 9H).

Example 676

5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 4-(2-bromo-5-(trifluoromethyl)benzyl)morpholine. MS (ESI): masscalcd. for C₂₁H₂₀F₃N₅O, 415.16; m/z found, 416.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.96 (s, 2H), 8.67 (dd, J=2.3, 0.9, 1H), 7.97 (dd, J=8.2,2.3, 1H), 7.89 (dd, J=8.2, 0.9, 1H), 7.86-7.84 (m, 1H), 7.72-7.65 (m,1H), 7.52 (d, J=7.9, 1H), 3.63-3.58 (m, 4H), 3.54-3.48 (m, 2H),2.41-2.28 (m, 4H).

Example 677

5-{5-[2-(Morpholin-4-ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (2-bromophenyl)(morpholino)methanone. MS (ESI): mass calcd. forC₂₀H₁₉N₅O₂, 361.15; m/z found, 362.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.96 (s, 2H), 8.69-8.64 (m, 1H), 7.95-7.87 (m, 2H), 7.64-7.59 (m, 1H),7.58-7.51 (m, 2H), 7.49-7.42 (m, 1H), 3.69-3.54 (m, 3H), 3.48-3.33 (m,2H), 3.20-3.07 (m, 1H), 2.97-2.80 (m, 2H).

Example 678

5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-bromo-2-methoxybenzene. MS (ESI): mass calcd. for C₁₆H₁₄N₄O.C₂HF₃O₂, 278.12; m/z found, 279.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.00(s, 2H), 8.81 (d, J=2.2, 1H), 8.28 (dd, J=8.4, 2.2, 1H), 8.02 (d, J=8.4,1H), 7.48-7.41 (m, 2H), 7.16 (d, J=8.4, 1H), 7.11 (m, 1H), 3.87 (s, 3H).

Example 679

5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-difluoropiperidine. MS (ESI): masscalcd. for C₂₀H₁₉F₂N₅O₂S, 431.12; m/z found, 432.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 9.06 (s, 2H), 8.62 (dd, J=2.1, 1.1, 1H), 8.12 (dd, J=8.0,1.3, 1H), 8.00-7.91 (m, 2H), 7.77 (m, 1H), 7.68 (m, 1H), 7.46 (dd,J=7.6, 1.4, 1H), 3.07 (t, J=11.3, 2H), 2.98-2.90 (m, 2H), 1.99-1.80 (m,2H), 1.70-1.55 (m, 2H).

Example 680

5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-difluoropyrrolidine. MS (ESI): masscalcd. for C₁₉H₁₇F₂N₅O₂S, 417.11; m/z found, 418.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 9.06 (s, 2H), 8.63 (m, 1H), 8.13 (dd, J=8.0, 1.3, 1H),7.99-7.92 (m, 2H), 7.78 (m, 1H), 7.69 (m, 1H), 7.48 (dd, J=7.6, 1.4,1H), 3.30-3.25 (m, 2H), 3.18 (t, J=7.3, 2H), 2.35-2.06 (m, 2H).

Example 681

5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)azepane. MS (ESI): mass calcd. forC₂₁H₂₃N₅O₂S, 409.16; m/z found, 410.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ9.05 (s, 2H), 8.62 (m, 1H), 8.01 (dd, J=7.8, 1.4, 1H), 7.98-7.92 (m,2H), 7.71 (m, 1H), 7.64 (m, 1H), 7.43 (dd, J=7.5, 1.4, 1H), 3.01-2.91(m, 4H), 1.65-1.51 (m, 8H).

Example 682

5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-4,4-difluoropiperidine. MS (ESI): masscalcd. for C₂₀H₁₉F₂N₅O₂S, 431.12; m/z found, 432.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 9.08 (s, 2H), 8.63 (m, 1H), 8.13 (dd, J=8.0, 1.3, 1H),7.96 (d, J=2.0, 2H), 7.77 (m, 1H), 7.68 (m, 1H), 7.47 (dd, J=7.5, 1.4,1H), 3.09-2.95 (m, 4H), 1.97-1.71 (m, 4H).

Example 683

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethylbenzenesulfonamidetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-bromo-N-ethylbenzenesulfonamide. MS (ESI): mass calcd. forC₁₇H₁₇N₅O₂S, 355.11; m/z found, 356.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ9.06 (s, 2H), 8.66 (dd, J=2.3, 0.9, 1H), 8.08 (dd, J=7.9, 1.4, 1H), 8.05(dd, J=8.3, 2.3, 1H), 7.97 (dd, J=8.3, 0.9, 1H), 7.72 (m, 1H), 7.65 (m,1H), 7.44 (dd, J=7.5, 1.4, 1H), 2.86 (q, J=7.2, 2H), 1.02 (t, J=7.2,3H).

Example 684

Example 142-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamidetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-bromo-N-(dicyclopropylmethyl)benzenesulfonamide. MS (ESI): masscalcd. for C₂₂H₂₃N₅O₂S, 421.16; m/z found, 422.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.99 (s, 2H), 8.65 (dd, J=2.3, 0.8, 1H), 8.16 (dd, J=7.9,1.3, 1H), 8.03 (dd, J=8.3, 2.3, 1H), 7.93 (dd, J=8.3, 0.8, 1H), 7.70(td, J=7.5, 1.4, 1H), 7.61 (m, 1H), 7.40 (dd, J=7.5, 1.3, 1H), 2.07 (t,J=8.3, 1H), 0.89-0.75 (m, 2H), 0.49-0.36 (m, 2H), 0.30-0.13 (m, 4H),0.00-−0.09 (m, 2H).

Example 685

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamidetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (S)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₅O₂S C₁₈H₁₆F₃N₅O₂S, 423.10; m/z found,424.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.06 (s, 2H), 8.64 (dd, J=2.2,0.9, 1H), 8.15 (dd, J=8.0, 1.3, 1H), 8.04 (dd, J=8.2, 2.2, 1H), 7.99(dd, J=8.2, 0.9, 1H), 7.73 (m, 1H), 7.66 (m, 1H), 7.43 (dd, J=7.6, 1.3,1H), 3.96-3.71 (m, 1H), 1.23 (d, J=7.0, 3H).

Example 686

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamidetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (R)-2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₅O₂S C₁₈H₁₆F₃N₅O₂S, 423.10; m/z found,424.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 9.05 (d, J=0.9, 2H), 8.63 (m,1H), 8.15 (dd, J=8.0, 1.3, 1H), 8.03-7.99 (m, 1H), 7.97 (m, 1H), 7.73(m, 1H), 7.65 (m, 1H), 7.42 (dd, J=7.5, 1.3, 1H), 3.91-3.81 (m, 1H),1.23 (d, J=7.0, 3H).

Example 687

4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulonyl)piperazin-2-one

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd.for C₁₉H₁₈N₆O₃S, 410.12; m/z found, 411.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.97 (s, 2H), 8.60 (dd, J=2.2, 0.9, 1H), 8.18 (dd, J=8.0, 1.3,1H), 7.91 (dd, J=8.2, 2.2, 1H), 7.87 (dd, J=8.2, 1.0, 1H), 7.80 (m, 1H),7.70 (m, 1H), 7.50 (dd, J=7.5, 1.3, 1H), 3.42 (s, 2H), 3.15 (s, 4H).

Example 688

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (S)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): masscalcd. for C₁₈H₁₉N₅O₃S, 385.12; m/z found, 386.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.92 (s, 2H), 8.61-8.57 (m, 1H), 8.09 (d, J=8.0, 1H), 7.91(dd, J=8.2, 2.3, 1H), 7.82 (d, J=8.2, 1H), 7.70 (m, 1H), 7.62 (m, 1H),7.41 (d, J=6.8, 1H), 3.70-3.61 (m, 1H), 2.79-2.66 (m, 2H), 1.04 (d,J=6.3, 3H).

Example 689

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): masscalcd. for C₁₈H₁₉N₅O₃S, 385.12; m/z found, 386.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.92 (s, 2H), 8.60 (dd, J=2.3, 0.8, 1H), 8.09 (dd, J=8.0,1.3, 1H), 7.91 (dd, J=8.2, 2.3, 1H), 7.82 (dd, J=8.2, 0.9, 1H), 7.70 (m,1H), 7.62 (m, 1H), 7.41 (dd, J=7.6, 1.4, 1H), 3.70-3.59 (m, 1H),2.79-2.67 (m, 2H), 1.04 (d, J=6.3, 3H).

Example 690

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₅O₃S, 439.09; m/z found, 440.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.96 (s, 2H), 8.64 (d, J=1.7, 1H), 8.39 (s,1H), 8.01 (d, J=8.0, 1H), 7.95 (dd, J=8.2, 2.3, 1H), 7.87 (d, J=8.3,1H), 7.64 (d, J=8.0, 1H), 3.46 (t, J=5.9, 2H), 2.91 (t, J=5.9, 2H).

Example 691

5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₁₈H₁₆N₄O₂S, 352.10; m/z found, 353.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ7.80 (s, 2H), 7.41-7.36 (m, 1H), 6.86 (dd, J=8.0, 1.2, 1H), 6.74-6.70(m, 1H), 6.69-6.64 (m, 1H), 6.50 (m, 1H), 6.42 (m, 1H), 6.20 (dd, J=7.5,1.2, 1H), 1.08-0.98 (m, 1H), −0.28-−0.39 (m, 4H).

Example 692

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamidetrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₈H₁₆F₃N₅O₂S, 423.10; m/z found, 424.1 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.95 (s, 2H), 8.62 (d, J=2.0, 1H), 8.35 (s, 1H), 8.01(d, J=9.9, 1H), 7.93 (dd, J=8.2, 2.3, 1H), 7.87 (d, J=8.2, 1H), 7.64 (d,J=7.9, 1H), 2.84 (q, J=7.2, 2H), 1.01 (t, J=7.2, 3H).

Example 693

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-bromo-N-(tert-butyl)benzenesulfonamide. MS (ESI): mass calcd. forC₁₉H₂₁N₅O₂S, 383.14; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.96 (s, 2H), 8.62 (dd, J=2.3, 0.9, 1H), 8.34 (d, J=1.8, 1H), 8.01 (dd,J=8.0, 1.6, 1H), 7.94 (dd, J=8.2, 2.3, 1H), 7.87 (dd, J=8.2, 0.9, 1H),7.65 (d, J=7.9, 1H), 2.84 (q, J=7.2, 2H), 1.01 (t, J=7.2, 3H).

Example 694

2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI):mass calcd. for C₁₈H₁₉N₅O₃S, 385.12; m/z found, 386.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.92 (s, 2H), 8.66-8.56 (m, 1H), 8.19 (dd, J=8.0,1.4, 1H), 7.95 (dd, J=8.2, 2.3, 1H), 7.83 (dd, J=8.2, 0.9, 1H), 7.72 (m,1H), 7.64 (m, 1H), 7.43 (dd, J=7.5, 1.4, 1H), 3.43-3.16 (m, 4H), 1.03(d, J=6.6, 3H).

Example 695

3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphehenyl-4-yl}pyrazine-2-carbonitriletrifluoroacetic acid salt

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. forC₂₁H₁₄FN₇O, 399.12; m/z found, 400.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.73-8.70 (m, 1H), 7.89-7.81 (m, 2H), 7.51-7.43 (m, 2H), 7.41-7.35 (m,4H), 7.23 (m, 1H).

Example 696

5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that describedfor Intermediate D with DME as a solvent, heating at 100° Celsius for 16hours and using 2-amino-5-bromopyrazine and4-bromo-2-fluorobenzeneboronic acid. MS (ESI): mass calcd. forC₁₆H₁₀BrF₂N₃, 361.00; m/z found, 362.0, 364.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.47 (s, 1H), 8.30 (d, J=1.4, 1H), 8.12-8.02 (m, 1H), 7.49-7.32(m, 5H), 6.37-5.94 (m, 1H), 6.15 (s, 2H).

Example 697

5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared in a manner similar to that describedfor Intermediate HF heating at 90° Celsius for 16 hours and using5-bromo-1H-pyrrolo[2,3-b]pyridine and 4-bromo-2-fluorobenzeneboronicacid. MS (ESI): mass calcd. for C₁₉H₁₁BrF₂N₂, 384.01; m/z found, 385.0,387.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.29 (s, 1H), 8.47 (s, 2H),7.60-7.50 (m, 2H), 7.50-7.34 (m, 5H), 6.73 (s, 1H).

Example 698

5-(3-fluoro-2-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that describedfor Example 850 using5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine and4-(trifluoromethyl)phenylboronic acid. MS (ESI): mass calcd. forC₁₈H₁₃F₄N₃O, 363.10; m/z found, 363.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.61-8.56 (m, 1H), 8.12 (d, J=1.5, 1H), 7.72-7.66 (m, 4H), 7.22 (dd,J=8.3, 1.4, 1H), 7.28-7.24 (m, 1H), 4.73 (s, 2H), 3.77 (d, J=1.2, 3H).

Example 699

5-(2′,3,4′-Trifluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amineand (2,4-difluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₆H₁₀F₃N₃, 301.08; m/z found, 302.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.43-8.35 (m, 1H), 8.03 (d, J=1.4, 1H), 7.97 (m, 1H), 7.73-7.65 (m, 1H),7.54-7.35 (m, 3H), 7.26-7.20 (m, 1H), 6.74 (s, 2H).

Example 700

racemic 5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Intermediate EB utilizing5-(3-fluoro-2′-(methylsulfinyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine. MS(ESI): mass calcd. for C₁₇H₁₄FN₃OS, 327.08; m/z found, 328.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.10-7.89 (m, 3H), 7.79-7.58 (m,2H), 7.51-7.28 (m, 3H), 6.75 (s, 2H), 2.49 (s, 3H).

Example 701

4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amineand (2-cyanophenyl)boronic acid. MS (ESI): mass calcd. for C₁₇H₁₁FN₄,290.10; m/z found, 291.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s,1H), 8.05-7.98 (m, 3H), 7.83 (m, 1H), 7.71 (d, J=7.6, 1H), 7.66-7.47 (m,3H), 6.77 (s, 2H).

1-(2-Bromophenyl)imidazolidin-2-one

To a solution of imidazolidin-2-one (86 mg, 1.0 mmol) in 1,4-dioxane (5mL) was added Cs₂CO₃ (651 mg, 2.00 mmol) and Pd(OAc)₂ (15 mg, 0.050mmol). The mixture was purged with N₂ several times. XantPhos (43 mg,0.075 mmol) and 1-bromo-2-iodobenzene 4 (280 mg, 1.00 mmol) were addedand the reaction mixture was stirred at 100° Celsius for 14 hours underan N₂ atmosphere. After cooling to rt, the mixture was concentrated todryness and the residue purified by FCC to give the title compound (60mg, 25% yield). MS (ESI): mass calcd. for C₉H₉N₂OBr 239.99, m/z found240.1 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.61 (m, 1H), 7.38-7.34 (m,2H), 7.25-7.19 (m, 1H), 3.94-3.89 (m, 2H), 3.66-3.61 (m, 2H).

Example 702

1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)imidazolidin-2-one

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)imidazolidin-2-one. MS (ESI): mass calcd. forC₁₉H₁₆FN₅O, 349.13; m/z found, 350.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.41 (s, 1H), 8.10 (s, 1H), 7.94 (m, 1H), 7.81-7.77 (m, 1H), 7.51-7.46(m, 5H), 3.51 (t, J=6.2, 2H), 3.37 (t, J=6.2, 2H).

Example 703

4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing(2′-(N-(tert-butyl)sulfamoyl)-3-fluoro-[1,1′-biphenyl]-4-yl)boronic acidand 2-amino-5-bromo-4-cyanopyrimidine. MS (ESI): mass calcd. forC₂₁H₂₀FN₅O₂S, 327.08; m/z found, 328.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.64-8.59 (m, 1H), 8.07 (dd, J=7.9, 1.4, 1H), 7.71-7.65 (m, 1H),7.65-7.59 (m, 2H), 7.57 (s, 2H), 7.45-7.39 (m, 2H), 7.36 (dd, J=7.8,1.7, 1H), 6.89 (s, 1H), 1.02 (s, 9H).

Example 704

6-Amino-3-{2′-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI):mass calcd. for C₂₁H₁₈FN₅O₄S₂, 487.08; m/z found, 488.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-δ₆) δ 8.26 (s, 1H), 8.08 (dd, J=8.0, 1.3, 1H), 7.83-7.77(m, 1H), 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 7.51 (dd, J=7.6, 1.3,1H), 7.44 (dd, J=10.9, 1.7, 1H), 7.40 (s, 2H), 7.35 (dd, J=7.9, 1.6,1H), 3.31-3.23 (m, 4H), 3.11-3.04 (m, 4H).

Example 705

1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-N-methylazetidine-3-carboxamide. MS(ESI): mass calcd. for C₂₁H₂₀FN₅O₃S, 441.13; m/z found, 441.9 [M+H]⁺. ¹HNMR (500 MHz, DMSO-δ₆) δ 8.52 (s, 2H), 8.02 (d, J=7.9, 1H), 7.84 (d,J=4.8, 1H), 7.79-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.55 (m, 1H),7.45 (d, J=7.5, 1H), 7.33 (d, J=11.7, 1H), 7.27 (d, J=7.8, 1H), 6.89 (s,2H), 3.70 (t, J=7.0, 2H), 3.63 (t, J=8.0, 2H), 3.19-3.08 (m, 1H), 2.56(d, J=4.4, 3H).

Example 706

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide. MS (ESI): mass calcd.for C₁₉H₁₆FNO₅₃S, 413.10; m/z found, 414.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-δ₆) δ 8.26 (s, 1H), 7.99 (dd, J=7.9, 1.4, 1H), 7.72-7.59 (m, 3H),7.47-7.41 (m, 2H), 7.41-7.31 (m, 4H), 4.70-4.64 (t, J=5.5, 1H),3.45-3.27 (m, 2H), 2.85-2.78 (m, 2H).

Example 707

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand S-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): masscalcd. for C₂₀H₁₈FN₅O₃S, 427.11; m/z found, 428.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-δ₆) δ 8.26 (s, 1H), 7.97 (dd, J=7.9, 1.4, 1H), 7.72-7.59 (m,3H), 7.49-7.43 (m, 2H), 7.41-7.33 (m, 4H), 4.71 (d, J=4.7, 1H),3.61-3.53 (m, 1H), 3.17 (d, J=5.3, 1H), 2.73-2.59 (m, 2H), 0.98 (d,J=6.2, 3H).

Example 708

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand R-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide.Characterization data were identical to the enantiomer (Example X).

Example 709

1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)piperidine-4-carboxamide. MS (ESI): masscalcd. for C₂₂H₂₂FN₅O₃S, 455.14; m/z found, 455.9 [M+H]⁺. ¹H NMR (500MHz, DMSO-δ₆) δ 8.51 (d, J=1.4, 2H), 8.02 (dd, J=8.0, 1.3, 1H),7.78-7.71 (m, 1H), 7.69-7.63 (m, 1H), 7.61-7.54 (m, 1H), 7.45 (dd,J=7.6, 1.4, 1H), 7.32 (dd, J=11.8, 1.7, 1H), 7.26 (dd, J=7.9, 1.8, 1H),7.17 (s, 1H), 6.88 (s, 2H), 6.73 (s, 1H), 3.26-3.19 (m, 2H), 2.47-2.38(m, 2H), 2.13-2.02 (m, 1H), 1.59 (dd, J=13.9, 3.8, 2H), 1.31-1.17 (m,2H).

Example 710

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand R-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): masscalcd. for C₂₀H₁₈FN₅O₃S, 426.11; m/z found, 427.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) 8.22 (s, 1H), 8.15 (dd, J=8.0, 1.4, 1H), 7.72-7.64 (m, 1H),7.64-7.56 (m, 2H), 7.46-7.33 (m, 3H), 3.46-3.36 (m, 1H), 3.30-3.25 (m,1H), 3.25-3.14 (m, 1H), 1.02 (d, J=6.6, 3H).

Example 711

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand S-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide.Characterization data were identical to the enantiomer (Example X).

Example 712

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₀H₁₅F₄N₅O₃S, 481.08; m/z found, 482.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-δ₆) δ 8.35-8.31 (m, 1H), 8.26 (s, 1H), 8.10-8.05(m, 1H), 7.91-7.86 (m, 1H), 7.71 (d, J=7.9, 1H), 7.68-7.63 (m, 1H), 7.46(dd, J=10.9, 1.7, 1H), 7.43-7.36 (m, 3H), 4.75 (t, J=5.4, 1H), 3.40-3.33(m, 2H), 2.88-2.78 (m, 2H).

Example 713

4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)-[1,1′-biphenyl]-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI):mass calcd. for C₂₀H₁₅F₄N₅O₂S, 465.09; m/z found, 465.8 [M+H]⁺. ¹H NMR(600 MHz, DMSO-δ₆) δ 8.26 (s, 2H), 8.11-8.07 (m, 1H), 7.87-7.81 (m, 1H),7.72 (d, J=7.9, 1H), 7.69-7.63 (m, 1H), 7.45 (dd, J=10.8, 1.7, 1H),7.43-7.36 (m, 3H), 2.78 (qd, J=7.2, 5.5, 2H), 0.97 (t, J=7.2, 3H).

Example 714

4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-bromo-N-(3-hydroxy-2,2-dimethylpropyl)benzenesulfonamide. MS(ESI): mass calcd. for C₂₂H₂₂FN₅OS, 455.14; m/z found, 456.0 [M+H]⁺. ¹HNMR (600 MHz, DMSO-δ₆) δ 8.26 (s, 1H), 7.93 (dd, J=7.8, 1.5, 1H),7.72-7.60 (m, 3H), 7.47 (dd, J=7.4, 1.5, 1H), 7.43-7.34 (m, 5H), 4.49(t, J=5.4, 1H), 3.08 (d, J=5.4, 2H), 2.62 (d, J=6.5, 2H), 0.73 (s, 6H).

Example 715

6-Amino-3-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 4-((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)piperazin-2-one. MS(ESI): mass calcd. for C₂₂H₁₆F₄N₆O₃S, 520.09; m/z found, 520.8 [M+H]⁺.¹H NMR (600 MHz, DMSO-δ₆) δ 8.29 (d, J=1.9, 1H), 8.26 (s, 1H), 8.19 (dd,J=8.2, 1.9, 1H), 8.07-8.01 (m, 1H), 7.77 (d, J=7.9, 1H), 7.70-7.64 (m,1H), 7.49 (dd, J=10.8, 1.7, 1H), 7.44-7.36 (m, 3H), 3.39 (s, 2H),3.07-2.96 (m, 4H).

Example 716

N-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide

The title compound was prepared using conditions analogous to those usedto make Example 337 utilizingN-(2-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)thio)ethyl)benzamide.MS (ESI): mass calcd. for C₂₅H₂₁FN₄O₃S, 476.13; m/z found, 477.0 [M+H]⁺.¹H NMR (600 MHz, DMSO) δ 8.52-8.46 (m, 3H), 8.11 (dd, J=7.8, 1.4, 1H),7.74-7.68 (m, 1H), 7.68-7.61 (m, 3H), 7.61-7.56 (m, 1H), 7.52-7.47 (m,1H), 7.43-7.38 (m, 3H), 7.36 (dd, J=11.7, 1.7, 1H), 7.30 (dd, J=7.9,1.7, 1H), 6.93 (s, 2H), 3.47-3.40 (m, 2H), 3.30-3.24 (t, J=6.7, 2H).

Example 717

1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3-dimethylbutan-2-one

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)-3,3-dimethylbutan-2-one. MS (ESI): masscalcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆) δ 8.51 (d, J=1.5, 2H), 8.09 (dd, J=8.0, 1.3, 1H),7.82-7.76 (m, 1H), 7.75-7.69 (m, 1H), 7.68-7.62 (m, 1H), 7.44 (dd,J=7.6, 1.3, 1H), 7.39-7.34 (dd, J=11.6, 1.8, 1H), 7.29 (dd, J=7.9, 1.7,1H), 6.96 (s, 2H), 4.44 (s, 2H), 0.94 (s, 9H).

Example 718

5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amineStep A: Ethyl3-(4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-ylthio)propanoate

A mixture of ethyl 3-((2-bromophenyl)thio)propanoate (5.8 g, 20 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine(6.95 g, 22.1 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (1.7 g, 2.0 mmol), Na₂CO₃ (4.25g, 40.1 mmol) and 1,4-dioxane/water (80 mL/10 mL) was stirred at 90° C.overnight under N₂. The reaction mixture was cooled to rt, filtered, andthe filtrate concentrated to dryness. The resultant residue wassubjected to FCC to give the title compound (6.5 g, 82%). MS (ESI): masscalcd. for C₂₁H₂₀FN₃O₂S, 397.13; m/z found, 397.9 [M+H]⁺.

Step B: 4′-(2-Aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-thiol

To a solution of ethyl3-(4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (6.5g, 16 mmol) in THF (70 mL) was added t-BuOK (3.68 g, 32.8 mmol) under aN₂ atmosphere. After stirring for 10 min, methanol (5 mL) was added andthe resulting mixture purified by FCC to give the title compound (4.8 g,16 mmol, 98%). MS (ESI): mass calcd. for C₁₆H₁₂FN₃S, 297.07; m/z found,298.1 [M+H]⁺.

Step C:5-(3-Fluoro-6′-(pyrimidin-2-ylthio)biphenyl-4-yl)pyrimidin-2-amine

A solution of 4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-thiol (300mg, 1.00 mmol), 2-chloropyrimidine (229 mg, 2.00 mmol), PPh₃ (262 mg,1.00 mmol) and TEA (0.38 mL) in DMF (10 mL) was stirred at 120° C. undera N₂ atmosphere over-night. The reaction mixture was then cooled to rt,concentrated to dryness, and the residue subjected to FCC purificationto give the title compound (170 mg, 45%). MS (ESI): mass calcd. forC₂₀H₁₄FN₅S, 375.10; m/z found, 375.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.66 (s, 2H), 8.56 (d, J=4.9, 2H), 7.79-7.73 (m, 1H), 7.63-7.56 (m, 2H),7.55-7.48 (m, 2H), 7.33-7.24 (m, 2H), 7.21 (t, J=4.9, 1H), 6.23 (s, 2H).

Step D:5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

To a rt solution of5-(3-fluoro-6′-(pyrimidin-2-ylthio)biphenyl-4-yl)pyrimidin-2-amine (100mg, 0.270 mmol), NaIO₄ (170 mg, 0.810 mmol) in CH₃CN/DCM/H₂O (5 mL/5mL/5 mL) was added RuCl₃ (6 mg, 0.03 mmol). The resultant mixture wasstirred for 3 h before diluting with saturated NaHCO₃ (15 mL). Theorganic solvent was removed in vacuo, and the resultant solid isolatedby filtration. The filter cake was washed with water, dried under vacuumand then subjected to HPLC purification to give the title compound (12mg, 11%). MS (ESI): mass calcd. for C₂₀H₁₄FN₅O₂S, 407.09; m/z found,408.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=4.8, 2H), 8.42 (s,2H), 8.33 (d, J=7.6, 1H), 7.86 (m, 1H), 7.80 (t, J=7.6, 1H), 7.74 (m,1H), 7.43 (d, J=7.1, 1H), 7.30 (m, 1H), 6.93 (s, 2H), 6.80 (d, J=11.7,1H), 6.75 (d, J=8.0, 1H).

Example 719

5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₄FN₅O₂S, 407.09; m/zfound, 408.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=2.3, 1H),8.71 (dd, J=2.3, 1.5, 1H), 8.55 (d, J=1.3, 1H), 8.44 (d, J=1.4, 2H),8.35 (dd, J=7.8, 1.4, 1H), 7.85 (m, 1H), 7.81 (m, 1H), 7.41 (dd, J=7.4,1.3, 1H), 7.34 (m, 1H), 6.95 (s, 2H), 6.80 (dd, J=7.9, 1.7, 1H), 6.75(dd, J=11.4, 1.6, 1H).

Example 720

5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₄FN₅O₂S, 407.09; m/zfound, 408.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (d, J=1.3, 1H),8.96 (d, J=5.1, 1H), 8.57 (s, 2H), 8.35 (dd, J=7.8, 1.3, 1H), 7.88 (m,1H), 7.83 (m, 1H), 7.58 (dd, J=5.1, 1.3, 1H), 7.44 (dd, J=7.4, 1.2, 1H),7.36 (m, 1H), 6.86-6.81 (m, 2H).

Example 721

5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 2H), 8.27-8.25(m, 2H), 7.83 (m, 1H), 7.78 (m, 1H), 7.56-7.35 (m, 4H), 6.97-6.87 (m,2H), 6.45 (s, 1H).

Example 722

5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 2H), 8.22 (d,J=7.7, 1H), 7.98 (d, J=5.8, 1H), 7.80 (m, 1H), 7.74 (m, 1H), 7.53 (s,2H), 7.41 (d, J=7.3, 1H), 7.36 (m, 1H), 7.01 (s, 2H), 6.89-6.84 (m, 2H),6.43 (d, J=5.9, 1H).

Example 723

5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 2H), 8.34 (dd,J=7.8, 1.5, 1H), 7.88 (d, J=1.2, 1H), 7.79-7.68 (m, 3H), 7.51 (m, 1H),7.34 (dd, J=7.3, 1.4, 1H), 7.04 (dd, J=7.9, 1.6, 1H), 6.98 (dd, J=11.4,1.5, 1H).

Example 724

4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 2H), 8.28 (d,J=4.8, 1H), 8.24 (d, J=7.6, 1H), 7.86-7.79 (m, 1H), 7.76 (m, 1H), 7.43(d, J=6.1, 1H), 7.36 (m, 1H), 7.25 (s, 2H), 6.98-6.83 (m, 4H), 6.50 (d,J=4.8, 1H).

Example 725

5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.36 (dd,J=7.8, 1.3, 1H), 7.96 (s, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.61 (s, 1H),7.47 (m, 1H), 7.38 (dd, J=7.4, 1.2, 1H), 7.03 (dd, J=7.9, 1.6, 1H), 6.96(dd, J=11.4, 1.5, 1H).

Example 726

6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.25-8.22(m, 2H), 8.02 (s, 1H), 7.85-7.71 (m, 2H), 7.65 (m, 1H), 7.42-7.39 (m,3H), 6.88 (s, 1H), 6.84 (d, J=7.2, 1H), 6.47 (s, 1H).

Example 727

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine

The title compound was prepared using conditions analogous to those usedto make Example 718. MS (ESI): mass calcd. for C₂₀H₁₅FN₆O₂S, 422.10; m/zfound, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.20 (d,J=7.2, 1H), 8.02 (s, 1H), 7.97 (d, J=5.7, 1H), 7.83-7.61 (m, 3H), 7.51(s, 2H), 7.41 (d, J=7.5, 1H), 6.89-6.82 (m, 2H), 6.43 (d, J=5.9, 1H).

Example 728

5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-bromo-2-((cyclopropylmethyl)sulfonyl)benzene. MS (ESI): masscalcd. for C₂₀H₁₈FN₃O₂S, 383.11; m/z found, 384.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.53 (d, J=1.5, 2H), 8.11 (dd, J=7.9, 1.2, 1H), 7.80 (m,1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.37 (dd,J=11.8, 1.7, 1H), 7.28 (dd, J=7.9, 1.7, 1H), 6.93 (s, 2H), 2.91 (d,J=7.2, 2H), 0.78-0.69 (m, 1H), 0.45-0.37 (m, 2H), 0.13-0.05 (m, 2H).

Example 729

6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₀H₁₅FN₄O₂S, 394.09; m/z found, 395.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-δ₆)δ 8.26 (s, 1H), 8.07 (dd, J=8.0, 1.3, 1H), 7.82-7.77 (m, 1H), 7.74-7.69(m, 1H), 7.66-7.62 (m, 1H), 7.52 (dd, J=7.6, 1.3, 1H), 7.44 (dd, J=10.8,1.7, 1H), 7.41-7.36 (m, 3H), 2.47-2.41 (m, 1H), 0.99-0.91 (m, 2H),0.90-0.83 (m, 2H).

1-((2-Bromophenyl)sulfonyl)cyclopentanecarbonitrile Step A:2-(2-Bromophenylthio)acetonitrile

A mixture of 2-bromobenzenethiol (6.3 mL, 53 mmol), K₂CO₃ (13.8 g, 100mmol) and 2-chloroacetonitrile (3.2 mL, 50 mmol) in DMF (50 mL) wasstirred at 25° C. for 6 h, poured into water (700 mL), and extractedwith petroleum ether (300 mL) followed by DCM (2×200 mL). The combinedDCM extracts were concentrated to dryness, and re-dissolved in petroleumether/ethyl acetate (10:1, 600 mL). The organic solution was washed withwater (250 mL) and brine (250 mL), dried over Na₂SO₄, filtered andconcentrated to dryness to give the title compound (11 g, 85%). ¹H NMR(300 MHz, CDCl₃) δ 7.67 (dd, J=7.8, 1.5, 1H), 7.60 (dd, J=7.8, 1.5, 1H),7.41 (m, 1H), 7.25 (m, 1H), 3.68 (s, 2H).

Step B: 2-(2-Bromophenylsulfonyl)acetonitrile

A mixture of 2-(2-bromophenylthio)acetonitrile (10.8 g, 47.4 mmol),NaIO₄ (30.4 g, 142 mmol) and RuCl₃ (4 mg) in DCM/ACN/H₂O (1:1:1, 300 mL)was stirred at rt for 18 h, and then filtered. The filtrate was dilutedwith water (600 mL), extracted with DCM (3×200 mL). The combined organicextracts were washed with brine (200 mL), dried over Na₂SO₄, filteredthrough a pad of silica gel, and concentrated to dryness to give thetitle compound (10.4 g, 84%). ¹HNMR (400 MHz, CDCl₃) δ 8.30-8.24 (m,1H), 7.88-7.82 (m, 1H), 7.11-7.62 (m, 2H), 4.48 (s, 2H).

Step C: 1-((2-Bromophenyl)sulfonyl)cyclopentanecarbonitrile

A mixture of 2-(2-bromophenylsulfonyl)acetonitrile (4.4 g, 17 mmol),tetrabutylammonium bromide (0.82 g, 2.6 mmol), 1,4-dibromobutane (3.85g, 17.8 mmol) and NaOH (14 mL, 5 N) in DCM (30 mL) was stirred at rt for5 h, before diluting with DCM (200 mL), washing with water (2×80 mL) andbrine (60 mL), drying over Na₂SO₄, filtering, and concentrating todryness. The residue was treated with IPA (20 mL) and sonicated beforeisolating the title compound (2.2 g) via vacuum filtration. The filtratewas concentrated to dryness and the resultant residue subjected to FCCto give additional title compound. MS (ESI): mass calcd. forC₁₂H₁₂BrFN₃O₂S, 312.98; m/z found, 314.0 [M+H]⁺. ¹HNMR (300 MHz, CDCl₃)δ 8.28 (dd, J=7.5, 1.5, 1H), 7.85 (dd, J=7.5, 1.5, 1H), 7.62-7.51 (m,2H), 2.80-2.68 (m, 2H), 2.34-2.22 (m, 2H), 2.02-1.81 (m, 4H).

2-((2-Bromophenyl)sulfonyl)-2-methylpropanenitrile

The title compound was prepared using conditions analogous to those usedto make 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile utilizingMeI in Step A.

1-(2-Bromophenylsulfonyl)cyclopentanecarboxamide

A 30% H₂O₂ solution (1.6 mL) was added drop-wise at rt to a mixture of1-(2-bromophenylsulfonyl)cyclopentanecarbonitrile (1.6 g, 5.1 mmol),K₂CO₃ (2.1 g, 15 mmol), and DMSO (5 mL). The mixture was stirred for 30min before diluting with water (40 mL) and isolating the precipitate viavacuum filtration. The precipitate was washed with water and air-driedto give the title compound (1.5 g, 89%). MS (ESI): mass calcd. forC₁₂H₁₉NO₃S, 330.99; m/z found, 331.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ7.99-7.95 (m, 1H), 7.89-7.84 (m, 1H), 7.64-7.51 (m, 4H), 2.41-2.25 (m,4H), 1.78-1.66 (m, 2H), 1.58-1.45 (m, 2H).

2-((2-Bromophenyl)sulfonyl)-2-methylpropanamide

The title compound was prepared using conditions analogous to those usedto make 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide starting with2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile.

Example 730

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile. MS (ESI): masscalcd. for C₂₂H₁₉FN₄O₂S, 422.12; m/z found, 423.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.21 (dd, J=8.0, 1.0, 1H), 8.03 (d, J=1.4,1H), 7.92 (m, 1H), 7.88-7.80 (m, 2H), 7.53 (d, J=7.6, 1H), 7.35 (dd,J=12.3, 1.5, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.74 (s, 2H), 2.21-2.04 (m,4H), 1.71-1.67 (m, 4H).

Example 731

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide. MS (ESI): masscalcd. for C₂₂H₂₁FN₄O₃S, 440.13; m/z found, 441.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.05 (s, 1H), 7.98 (d, J=7.8, 1H), 7.86(m, 1H), 7.76 (m, 1H), 7.65 (m, 1H), 7.46 (s, 1H), 7.37 (d, J=7.4, 2H),7.26-7.23 (m, 2H), 6.77 (s, 2H), 2.20 (s, 2H), 2.05-1.88 (m, 2H), 1.56(s, 2H), 1.43 (s, 2H).

Example 732

2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): masscalcd. for C₂₀H₁₇FN₄O₂S, 396.11; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.62 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.84(m, 1H), 7.59 (m, 1H), 7.52 (d, J=7.5, 1H), 7.40 (dd, J=11.8, 1.1, 1H),7.31 (dd, J=7.9, 1.4, 1H), 1.51 (s, 6H).

Example 733

2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.68 (s, 2H), 7.97 (d, J=7.9, 1H), 7.79 (m, 1H), 7.68(m, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.36 (d, J=7.5, 1H), 7.32-7.29 (m,2H), 7.26 (d, J=7.9, 1H), 1.32 (s, 6H).

Example 734

5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineStep A: 2-(2-Bromophenylsulfonyl)-2-methylpropan-1-amine

BH₃.THF (4 mL, 1 M in THF) was added drop-wise to a solution of2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile (258 mg, 1.00 mmol)in THF (1 mL) at rt. The mixture was refluxed for 4 hours and thencooled to rt. Aqueous HCl (5 mL, 6 N) was added and stirring continuedfor an additional 1 hour. The mixture was basified to pH=9 by additionof NaOH (6 N), diluted with water (20 mL), and extracted with DCM (3×20mL). The combined extracts were washed with water (2×30 mL) and brine(60 mL), dried over Na₂SO₄, filtered, and concentrated to dryness togive the crude title compound (203 mg, 70%), which was used in thesubsequent step without further purification. MS (ESI): mass calcd. forC₁₀H₁₄NO₂S, 290.99; m/z found, 292.1 [M+H]⁺.

Step B: tert-Butyl 2-(2-bromophenylsulfonyl)-2-methylpropylcarbamate

A mixture of 2-(2-bromophenylsulfonyl)-2-methylpropan-1-amine (203 mg,0.700 mmol) and di-tert-butyl dicarbonate (152 mg, 0.700 mmol) in MeOH(10 mL) was stirred at 50° C. for 6 hours, cooled to rt, and thenconcentrated to dryness. The resulting residue was subjected to FCCpurification to give the title compound (180 mg, 65%). MS (ESI): masscalcd. for C₁₅H₂₂NO₄S, 391.05; m/z found, 291.8 [M-Boc+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.05 (dd, J=7.8, 1.7, 1H), 7.80 (dd, J=7.7, 1.0, 1H),7.56-7.50 (m, 1H), 7.52-7.42 (m, 1H), 5.51 (s, 1H), 3.52 (d, J=6.4, 2H),1.45 (s, 9H), 1.37 (s, 6H).

Step C: tert-Butyl2-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylsulfonyl)-2-methylpropylcarbamate

A mixture of K₂CO₃ (55 mg, 0.40 mmol) and dry DMF (5 mL) was spargedwith N₂ for 2 minutes and then treated with tert-butyl2-(2-bromophenylsulfonyl)-2-methylpropylcarbamate (78 mg, 0.20 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(66 mg, 0.21 mmol), t-BuXphos (14 mg, 0.020 mmol) and Pd₂(dba)₃ (18 mg,0.020 mmol). The resulting mixture was purged with N₂ several times, andthen stirred at 80° C. overnight. The reaction mixture was cooled to rt,diluted with EtOAc (20 mL), and filtered. The filtrate was concentratedto dryness and subjected to FCC to give the title compound (52 mg, 52%).MS (ESI): mass calcd. for C₂₅H₂₉N₄O₄S, 500.19; m/z found, 501.1 [M+H]⁺.

Step D:5-(6′-(1-Amino-2-methylpropan-2-ylsulfonyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine

To a solution of tert-butyl2-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylsulfonyl)-2-methylpropylcarbamate (52 mg, 0.10 mmol) in DCM (5 mL) was added TFA (2 mL). Theresulting mixture was stirred at rt overnight then concentrated todryness. The residue was basified to pH ˜7-8 by addition of saturatedNaHCO₃. The resulting mixture was diluted with water (30 mL), extractedwith DCM (3×10 mL), and the combined extracts washed with brine (20 mL),concentrated to dryness, and the resultant crude product purified byHPLC to give the title compound. MS (ESI): mass calcd. for C₂₀H₂₁FN₄O₂S,400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 2H),8.18 (d, J=7.9, 1H), 7.90-7.86 (m, 1H), 7.80-7.76 (m, 1H), 7.68-7.64 (m,1H), 7.50 (d, J=7.6, 1H), 7.40 (d, J=3.1, 1H), 7.38 (s, 1H), 3.18 (s,2H), 1.22 (s, 6H).

Example 735

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): masscalcd. for C₂₀H₁₇FN₄O₂S, 396.11; m/z found, 397.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.18 (d, J=8.0, 1H), 8.12 (d, J=1.2, 1H),7.94 (m, 1H), 7.88-7.82 (m, 2H), 7.54 (d, J=7.6, 1H), 7.37 (dd, J=12.4,1.4, 1H), 7.29 (dd, J=8.1, 1.6, 1H), 1.50 (s, 6H).

Example 736

2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-((2-bromophenyl)sulfonyl)-2-methylpropanamide. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.16 (d, J=1.2, 1H), 7.96 (dd, J=8.0, 0.9,1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.72-7.64 (m, 1H), 7.44 (s, 1H), 7.37(dd, J=7.6, 0.9, 1H), 7.34 (s, 1H), 7.27 (dd, J=6.4, 1.3, 1H), 7.24 (s,1H), 1.31 (s, 6H).

Example 737

5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 6 using-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-((2-bromophenyl)sulfonyl)-2-methylpropan-1-amine. MS (ESI): masscalcd. for C₂₀H₂₁FN₄O₂S, 400.14; m/z found, 401.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.40 (s, 1H), 8.11 (d, J=6.9, 1H), 8.08 (d, J=1.4, 1H),7.89-7.85 (m, 1H), 7.82-7.78 (m, 1H), 7.72-7.68 (m, 1H), 7.47 (d, J=6.5,1H), 7.30-7.26 (m, 2H), 2.77 (s, 2H), 1.12 (s, 6H).

Example 738

1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile. MS (ESI): masscalcd. for C₂₂H₁₉FN₄O₂S, 422.12; m/z found, 423.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.52 (s, 2H), 8.21 (d, J=8.0, 1H), 7.91 (m, 1H),7.86-7.79 (m, 1H), 7.57 (m, 1H), 7.52 (d, J=7.6, 1H), 7.37 (dd, J=11.8,1.4, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.92 (s, 2H), 2.22-2.07 (m, 4H),1.72-1.68 (m, 4H).

Example 739

1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 1-(2-bromophenylsulfonyl)cyclopentanecarboxamide. MS (ESI): masscalcd. for C₂₂H₂₁FN₄O₃S, 440.13; m/z found, 441.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.52 (s, 2H), 7.98 (d, J=7.7, 1H), 7.75 (m, 1H), 7.65(m, 1H), 7.54 (m, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 2H), 7.28-7.22 (m,2H), 6.93 (s, 2H), 2.27-2.16 (m, 2H), 2.04-1.91 (m, 2H), 1.57 (s, 2H),1.49-1.35 (m, 2H).

Example 740

5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 65-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand (1-((2-bromophenyl)sulfonyl)cyclopentyl)methanamine. MS (ESI): masscalcd. for C₂₂H₂₃FN₅O₂S, 426.15; m/z found, 427.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.54 (d, J=1.3, 2H), 8.20 (dd, J=7.9, 1.2, 1H), 7.83 (m,1H), 7.73 (m, 1H), 7.57-7.46 (m, 2H), 7.35-7.32 (m, 2H), 2.92 (s, 2H),2.13-1.99 (m, 2H), 1.65-1.42 (m, 6H).

Example 741

5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718, Steps A-C using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-aminein Step A and 2-amino-5-chloropyrazine in Step C. MS (ESI): mass calcd.for C₁₉H₁₆FN₅O₃S, 390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.94-7.86 (m, 3H), 7.33-7.28 (m,5H), 7.12-7.06 (m, 1H).

Example 742

5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718, Steps A-C using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-aminein Step A and 2-amino-6-chloropyrazine in Step C. MS (ESI): mass calcd.for C₂₀H₁₅FN₆S, 390.11; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.28 (s, 1H), 8.21 (s, 1H), 7.84 (m, 1H), 7.73-7.65 (m, 1H), 7.58-7.41(m, 5H), 7.28-7.21 (m, 2H), 7.20-7.10 (m, 2H)

Example 743

5-(3-Fluoro-2′-(pyrimidin-4-ylthio)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718, Steps A-C using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-aminein Step A and 4-chloropyrimidine in Step C. MS (ESI): mass calcd. forC₂₀H₁₄FN₅S, 375.10; m/z found, 375.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.73 (s, 1H), 8.32 (d, J=5.7, 1H), 8.28 (m, 1H), 8.19 (d, J=1.4, 1H),7.85 (m, 1H), 7.81-7.74 (m, 1H), 7.72-7.63 (m, 1H), 7.63-7.53 (m, 2H),7.31-7.18 (m, 2H), 6.90 (dd, J=5.6, 1.3, 1H).

Example 744

5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 718, Steps A-C using 2-amino-5-chloropyrazine in Step C.MS (ESI): mass calcd. for C₂₀H₁₅FN₆S, 390.11; m/z found, 391.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=1.4, 2H), 7.79 (d, J=1.4, 1H), 7.72(d, J=1.4, 1H), 7.47 (m, 1H), 7.32-7.17 (m, 6H).

Example 745

6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-(2-bromophenoxy)pyrimidin-4-amine. MS (ESI): mass calcd. forC₂₁H₁₄FN₇OS₂, 399.12; m/z found, 400.2 [M+H]⁺. ¹H NMR (600 MHz, DMSO-δ₆)δ 8.22 (s, 1H), 7.79 (d, J=5.8, 1H), 7.62-7.51 (m, 2H), 7.49-7.38 (m,3H), 7.38-7.30 (m, 3H), 7.20 (dd, J=8.0, 1.2, 1H), 7.01 (s, 2H), 6.10(d, J=5.8, 1H).

Example 746

6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine. MS (ESI): masscalcd. for C₂₂H₁₂F₄N₆O, 452.10; m/z found, 453.1 [M+H]⁺. ¹H NMR (600MHz, DMSO-δ₆) δ 8.56 (d, J=4.8, 2H), 8.20 (s, 1H), 7.89-7.81 (m, 2H),7.81-7.75 (m, 1H), 7.61-7.54 (m, 1H), 7.48 (dd, J=11.1, 1.7, 1H), 7.43(dd, J=8.1, 1.7, 1H), 7.37 (s, 2H), 7.22-7.17 (m, 1H).

Example 747

6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrile

The title compound was prepared using conditions analogous to those usedto make Example 6 utilizing6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrileand 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. for C₂₁H₁₃FN₆O,384.11; m/z found, 385.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO-δ₆) δ 8.55 (d,J=4.8, 2H), 8.20 (s, 1H), 7.61 (dd, J=7.7, 1.7, 1H), 7.57-7.49 (m, 2H),7.44-7.37 (m, 3H), 7.35 (s, 2H), 7.32 (dd, J=8.1, 1.2, 1H), 7.19-7.15(m, 1H).

Example 748

N-(tert-Butyl)-3′-fluoro-4′-(5-(methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamideStep A:N-(tert-Butyl)-3′-fluoro-4′-(5-(N-(methylsulfonyl)methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide

To a 20 mL vial were added a stir-bar,4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide(49 mg, 0.12 mmol), dry DCM (2.0 mL), DIPEA, (0.10 mL, 0.58 mmol), andmethanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirredat rt for 17.25 h before subjecting it to FCC to give impure titlecompound. The product was used in the next step without furtherpurification.

Step B:N-(tert-Butyl)-3′-fluoro-4′-(5-(methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide

To a 20 mL vial containingN-(tert-butyl)-3′-fluoro-4′-(5-(N-(methylsulfonyl)methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide(38 mg, 0.068 mmol) were added a stir-bar and DMSO (1 mL). The mixturewas sonicated until homogeneous, and then treated with NaOH (0.23 mL,0.23 mmol, 1.0 N). The mixture was stirred at rt for 18.7 h beforepassing it through a syringe filter and subjecting it to HPLCpurification thus yielding the title compound (28 mg, 86%). MS (ESI):mass calcd. for C₂₁H₂₃FN₄O₄S₂, 478.11; m/z found, 479.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-δ₆) δ 11.29 (s, 1H), 8.82-8.72 (m, 1H), 8.46 (d, J=1.5,1H), 8.07 (dd, J=7.9, 1.4, 1H), 7.98-7.91 (m, 1H), 7.71-7.65 (m, 1H),7.65-7.58 (m, 1H), 7.43-7.32 (m, 3H), 7.05 (s, 1H), 3.41 (s, 3H), 1.03(s, 9H).

Example 749

5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-aminehydrogen chloride salt Step A:5-(6′-(Chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine

A mixture of(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanol (1.8g, 6.1 mmol) and SOCl₂ (6 mL) in DCM (20 mL) was stirred at 70° C. for 4h. The reaction mixture was cooled to rt and concentrated to dryness togive the title compound (1.86 g, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.40(s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.66-7.57 (m, 1H), 7.51-7.42 (m,2H), 7.40-7.30 (m, 3H), 6.89-6.62 (m, 2H), 4.73 (s, 2H).

Step B: S-(4′-(5-Aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methylethanethioate

A mixture of 5-(6′-(chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine(1.86 g, 5.94 mmol) and KSAc (0.81 g, 7.1 mmol) in 1,4-dioxane/H₂O (30mL/6 mL) was stirred at rt for 2 h. The solvent was then removed invacuo and the residue purified by FCC to give the title compound (1.42g, 68%). MS (ESI): mass calcd. for C₁₉H₁₆FN₃OS, 353.10; m/z found, 353.9[M+H]⁺.

Step C: 5-(2′-(Ethylthiomethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine

To a solution ofS-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methyl ethanethioate(100 mg, 0.280 mmol) in CH₃OH (30 mL) were added Ph₃P (150 mg, 0.560mmol), K₂CO₃ (78 mg, 0.56 mmol), and bromoethane [drop-wise addition (60mg, 0.56 mmol)] at rt. The reaction mixture was stirred at rt for 16 h,before removing the solvent in vacuo. The crude product was purifiedfirst by preparative-TLC followed by HPLC to give the title compound (70mg HCOOH salt, 73%).

Step D:5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

A mixture of5-(2′-(ethylthiomethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine (70 mg,0.21 mmol), m-CPBA (107 mg, 0.618 mmol) and TFA (0.2 mL) in dry DCM (20mL) was stirred at rt for 5 h, and then the solvent was removed undervacuum. The residue was purified by HPLC to give the title compound (40mg, 52%). MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₂S, 371.11; m/z found,371.9 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.68 (d, J=1.2, 1H), 8.26 (d,J=1.3, 1H), 8.15 (m, 1H), 7.70-7.61 (m, 1H), 7.53-7.31 (m, 5H), 4.43 (s,2H), 2.97 (q, J=7.4, 2H), 1.20 (t, J=7.4, 3H).

Example 750

5-{3-Fluoro-2′-[(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 749 utilizing 2-iodomethane in Step C. MS (ESI): masscalcd. for C₁₈H₁₆FN₃O₂S, 357.09; m/z found, 357.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.66 (d, J=1.4, 1H), 8.26 (d, J=1.3, 1H), 8.14 (m, 1H),7.70-7.61 (m, 1H), 7.54-7.45 (m, 2H), 7.43-7.32 (m, 3H), 4.49 (s, 2H),2.83 (s, 3H).

Example 751

5-(3-Fluoro-2′-{[(1-methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 749 utilizing 2-iodopropane in Step C. MS (ESI): masscalcd. for C₂₀H₂₀FN₅O₃S, 385.13; m/z found, 386.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.72-8.61 (m, 1H), 8.24 (s, 1H), 8.13 (m, 1H), 7.70-7.59(m, 1H), 7.54-7.28 (m, 5H), 4.40 (s, 2H), 3.18-3.07 (m, 1H), 1.23 (d,J=6.8, 6H).

Example 752

5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared using conditions analogous to those usedto make Example 749 utilizing5-(3-fluoro-2′-((pyrimidin-2-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminein Step D. MS (ESI): mass calcd. for C₂₁H₁₆FN₅O₂S, 421.10; m/z found,422.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.91 (d, J=4.9, 2H), 8.41 (s,1H), 8.11 (d, J=1.3, 1H), 7.90 (t, J=8.1, 1H), 7.71 (m, 1H), 7.66-7.59(m, 1H), 7.52-7.40 (m, 2H), 7.34 (dd, J=7.3, 1.5, 1H), 7.27-7.14 (m,2H), 5.02 (s, 2H).

Example 753

2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin-4-amine

The title compound was prepared using conditions analogous to those usedto make Example 749, Steps A-C utilizing 4-amino-2-chloropyrimidine. MS(ESI): mass calcd. for C₂₁H₁₇FN₆S, 404.12; m/z found, 405.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.63 (d, J=1.1, 1H), 8.25 (d, J=1.2, 1H), 8.10(m, 1H), 7.86 (d, J=7.2, 1H), 7.68-7.58 (m, 1H), 7.51-7.39 (m, 2H),7.37-7.23 (m, 3H), 6.40 (d, J=7.2, 1H), 4.62 (s, 2H).

Example 754

racemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing racemic 2-(trifluoromethyl)morpholine. MS (ESI): mass calcd.for C₂₂H₁₈F₄N₄O₂, 446.14; m/z found, 447.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) Complex due to the presence of multiple conformations on the NMRtime-scale, peaks listed for identification purposes only: δ 8.61 (s),8.18-7.95 (m), 7.59-7.29 (m), 4.88-4.41 (m), 4.11-3.51 (m), 3.32 (m),3.17-3.00 (m), 3.00-2.84 (m), 2.68-2.41 (m), 2.37-2.16 (m).

Example 755

1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing 3-hydroxyazetidine. MS (ESI): mass calcd. for C₂₀H₁₇FN₄O₂,364.13; m/z found, 364.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s,1H), 8.02 (s, 1H), 7.93-7.89 (m, 1H), 7.55-7.38 (m, 4H), 7.36-7.24 (m,2H), 6.67 (s, 2H), 5.64 (s, 1H), 4.28 (s, 1H), 4.08-4.01 (m, 1H),3.79-3.75 (m, 1H), 3.58-3.54 (m, 1H), 3.15 (s, 1H).

Example 756

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-carboxamide

The title compound was prepared as described in Step C of Example 504utilizing tetrahydro-2H-pyran-4-amine. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂, 392.16; m/z found, 392.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.33 (s, 1H), 8.22 (d, J=7.7, 1H), 8.01 (d, J=1.1, 1H), 7.86-7.82 (m,1H), 7.54-7.38 (m, 4H), 7.29-7.25 (m, 2H), 6.65 (s, 2H), 3.86-3.77 (m,1H), 3.73-3.70 (m, 2H), 3.26 (s, 2H), 1.61-1.59 (m, 2H), 1.38-1.28 (m,2H).

Example 757

5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. forC₂₂H₁₈F₄N₄O₃S, 494.10; m/z found, 494.7 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.36 (s, 1H), 8.02-7.90 (m, 4H), 7.78-7.76 (m, 1H), 7.36-7.29(m, 2H), 6.75 (s, 2H), 4.35-4.20 (m, 1H), 3.59-3.46 (m, 2H), 3.31-3.12(m, 4H), 3.04-2.90 (m, 1H).

Example 758

1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(Diastereomeric Mixture)

The title compound was prepared as described in Step C of Example 504utilizing a diastereomeric mixture of 1-(piperidin-3-yl)ethanolgivingthe title compound. MS (ESI): mass calcd. for C₂₃H₂₃FN₄O₃, 422.18; m/zfound, 422.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ Complex due to thepresence of multiple conformations on the NMR time-scale anddiastereoisomers, peaks listed for identification purposes only: 8.30(s), 8.01-7.80 (m), 7.53-7.14 (m), 4.55-4.49 (m), 4.33-4.25 (m),3.90-3.66 (m), 3.61-3.31 (m), 3.25 (s), 3.16-2.85 (m), 2.84-2.12 (m),1.07-0.76 (m).

Example 759

1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(diastereomeric mixture)

The title compound was prepared as described in Step C of Example 504utilizing a diastereomeric mixture of 1-(piperidin-3-yl)ethanol. MS(ESI): mass calcd. for C₂₃H₂₃FN₄O₃, 422.18; m/z found, 422.9 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) Complex due to the presence of multipleconformations on the NMR time-scale and diastereoisomers, peaks listedfor identification purposes only: δ 8.43 (s), 7.57-7.17 (m), 4.55-4.49(m), 4.32-4.26 (m), 3.89-3.70 (m), 3.61-3.33 (m), 3.33-3.23 (m),3.12-2.86 (m), 2.85-2.12 (m), 1.10-0.77 (m).

Example 760

4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide

The title compound was prepared as described in Step C of Example 504utilizing ethanolamine. MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₂, 352.13;m/z found, 352.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.06(d, J=1.2, 1H), 7.94-7.83 (m, 1H), 7.59-7.39 (m, 4H), 7.38-7.22 (m, 2H),3.51 (t, J=6.1, 2H), 3.35-3.31 (m, 2H).

Example 761

4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide

The title compound was prepared as described in Step C of Example 504utilizing ethanolamine. MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₂, 352.13;m/z found, 352.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 2H),7.57-7.42 (m, 5H), 7.34-7.27 (m, 5H), 3.52 (t, J=6.0, 2H), 3.35-3.31 (m,2H).

Example 762

(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (R)-3-hydroxypiperidine. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂, 392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃)Complex due to the presence of multiple conformations on the NMRtime-scale, peaks listed for identification purposes only: δ 8.37 (s),8.09 (br s), 8.03-7.87 (m), 7.65-7.45 (m), 7.45-7.23 (m), 4.34-4.20 (m),4.13-4.09 (m), 3.94-3.80 (m), 3.68-3.31 (m), 3.21-2.84 (m), 2.79-2.48(m), 1.94-1.65 (m), 1.39-1.08 (m).

Example 763

(cis/trans)4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide

The title compound was prepared as described in Step C of Example 504utilizing (cis/trans) 4-aminocyclohexanol. MS (ESI): mass calcd. forC₂₃H₂₃FN₄O₂, 406.18; m/z found, 407.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.36 (s, 1H), 8.07-8.04 (m, 1H), 7.88 (m, 1H), 7.57-7.40 (m, 4H),7.33-7.24 (m, 2H), 3.69-3.62 (m, 1H), 3.46-3.39 (m, 4H), 3.34 (br s,1H), 1.87-1.76 (m, 4H), 1.33-1.26 (m, 2H), 1.18-1.08 (m, 2H).

Example 764

(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (R)-piperidin-3-ol. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.52-8.51 (m), 7.59-7.47 (m),7.44-7.28 (m), 4.30-4.04 (m), 3.93-3.81 (m), 3.69-3.32 (m), 3.17-2.89(m), 2.83-2.57 (m), 1.96-1.67 (m), 1.53-1.15 (m).

Example 765

(cis/trans)4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide

The title compound was prepared as described in Step C of Example 504utilizing (cis/trans) 4-aminocyclohexanol. MS (ESI): mass calcd. forC₂₃H₂₃FN₄O₂, 406.18; m/z found, 407.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.49 (d, J=1.2, 2H), 7.58-7.40 (m, 5H), 7.33-7.26 (m, 2H), 3.69-3.61 (m,1H), 3.51-3.38 (m, 1H), 3.33 (br s, 1H), 1.88-1.76 (m, 4H), 1.35-1.27(m, 2H), 1.14 (m, 2H).

Example 766

racemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing racemic 2-(trifluoromethyl)morpholine. MS (ESI): mass calcd.for C₂₂H₁₈F₄N₄O₂, 446.14; m/z found, 447.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) Complex due to the presence of multiple conformations on the NMRtime-scale, peaks listed for identification purposes only: δ 8.57 (s),7.62-7.27 (m), 5.21 (s), 4.74 (dd), 4.52 (d), 4.12-3.73 (m), 3.65 (d),3.48-3.21 (m), 3.21-3.01 (m), 2.94 (m), 2.60 (m), 2.35 (s), 2.16 (s).

Example 767

(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (S)-piperidin-3-ol. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.51 (d), 7.64-7.45 (m),7.43-7.29 (m), 4.31-4.03 (m), 3.94-3.80 (m), 3.69-3.58 (m), 3.51-3.35(m), 3.34 (s), 3.22-2.84 (m), 2.84-2.56 (m), 2.44 (dd), 2.10-1.55 (m),1.52-1.15 (m).

Example 768

(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (S)-piperidin-3-ol. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.38 (s), 8.07 (s), 7.97-7.87(m), 7.59-7.45 (m), 7.44-7.25 (m), 4.30-4.27 (m), 4.11 (dd), 4.30-4.27(m), 3.66-3.56 (m), 3.49-3.32 (m), 3.20-2.83 (m), 2.79-2.50 (m), 2.36(dd), 2.04-1.58 (m), 1.50-1.13 (m).

Example 769

(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (R)-pyrrolidin-3-ol. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂,378.15; m/z found, 379.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.39 (s), 8.00 (s), 7.89-7.79(m), 7.45-7.22 (m), 5.13 (m), 4.30 (m), 4.14 (m), 3.70-3.36 (m),3.02-2.96 (m), 2.59 (m), 1.90-1.55 (m).

Example 770

(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (R)-pyrrolidin-3-ol. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂,378.15; m/z found, 379.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.46 (d), 7.46-7.23 (m), 5.47(m), 4.31 (m), 4.16 (m), 3.65-3.37 (m), 3.13-2.86 (m), 2.81 (m),1.86-1.60 (m).

Example 771

(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (S)-pyrrolidin-3-ol. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂,378.15; m/z found, 378.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.28 (s), 7.96 (s), 7.87-7.78(m), 7.51-7.18 (m), 4.25-4.16 (m), 4.05 (m), 3.58-3.29 (m), 3.20 (m),3.11-2.77 (m), 1.73 (m), 1.60 (m).

Example 772

(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol

The title compound was prepared as described in Step C of Example 504utilizing (S)-pyrrolidin-3-ol. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂,378.15; m/z found, 379.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due tothe presence of multiple conformations on the NMR time-scale, peakslisted for identification purposes only: δ 8.45 (d), 7.45-7.23 (m), 5.19(m), 4.33 (m), 4.17 (m), 3.63-3.56 (m), 3.50 (d), 3.06-2.87 (m), 1.79(m), 1.67 (m).

Example 773

5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine(diastereoisomeric mixture)

The title compound was prepared as described in Step C of Example 504utilizing a diastereoisomeric mixture of 2,6-dimethylmorpholine. MS(ESI): mass calcd. for C₂₃H₂₃FN₄O₂, 406.18; m/z found, 407.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) Complex due to the presence of multiplediastereoisomers and conformations on the NMR time-scale, peaks listedfor identification purposes only: δ 8.58 (d), 8.11 (s), 8.09-8.00 (m),7.55-7.29 (m), 4.77 (br s), 4.52 (d), 3.64-3.30 (m), 3.10-3.00 (m),2.58-2.47 (m), 2.44-2.33 (m), 2.18-2.01 (m), 1.14 (dd), 0.97-0.84 (m).

Example 774

5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (S)-3-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d,J=9.6, 1H), 8.04 (s, 1H), 8.00-7.91 (m, 1H), 7.61-7.45 (m, 3H),7.45-7.20 (m, 3H), 6.75 (d, J=5.1, 2H), 4.54-4.01 (m, 1H), 3.77-3.39 (m,2H), 3.25-3.15 (m, 1H), 3.05-2.85 (m, 1H), 2.85-2.63 (m, 1H), 2.22-1.95(m, 1H), 1.20 (d, J=6.9, 3H).

Example 775

5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (R)-3-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d,J=9.6, 1H), 8.04 (s, 1H), 8.01-7.89 (m, 1H), 7.61-7.46 (m, 3H),7.45-7.19 (m, 3H), 6.75 (d, J=5.1, 2H), 4.53-4.03 (m, 1H), 3.73-3.58 (m,1H), 3.54-3.41 (m, 1H), 3.25-3.15 (m, 1H), 3.05-2.86 (m, 1H), 2.84-2.64(m, 1H), 2.23-1.88 (m, 1H), 1.20 (d, J=6.9, 3H).

Example 776

5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (S)-2-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s,1H), 8.04 (s, 1H), 7.97-7.95 (m, 1H), 7.65-7.46 (m, 3H), 7.45-7.24 (m,3H), 6.76 (s, 2H), 4.27 (dd, J=23.7, 13.0, 1H), 3.87-3.38 (m, 2H),3.13-2.70 (m, 2H), 2.63-2.42 (m, 1H), 2.19-1.90 (m, 1H), 1.04 (d, J=6.0,3H).

Example 777

5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (S)-2-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d,J=5.2, 2H), 7.76-7.60 (m, 1H), 7.60-7.46 (m, 3H), 7.46-7.22 (m, 3H),6.76 (s, 2H), 4.27 (dd, J=20.9, 12.6, 1H), 3.88-3.52 (m, 1H), 3.43 (m,1H), 3.17-2.82 (m, 2H), 2.81-2.52 (m, 1H), 2.31-1.97 (m, 1H), 1.05 (d,J=5.9, 3H).

Example 778

5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (S)-3-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.54-8.45(m, 2H), 7.72-7.60 (m, 1H), 7.57-7.47 (m, 3H), 7.42-7.21 (m, 3H), 6.94(d, J=6.0, 2H), 4.48 (s, 1H), 3.90 (dd, J=13.9, 11.2, 1H), 3.60 (d,J=11.4, 1H), 3.16 (s, 1H), 3.01-2.68 (m, 2H), 2.27-1.96 (m, 1H), 1.20(d, J=6.8, 3H)

Example 779

5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared as described in Step C of Example 504utilizing (R)-3-methylmorpholine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂,392.16; m/z found, 393.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d,J=11.5, 2H), 7.69-7.58 (m, 1H), 7.56-7.42 (m, 3H), 7.40-7.18 (m, 3H),6.91 (d, J=5.8, 2H), 4.41 (d, J=21.0, 1H), 3.87 (dd, J=13.5, 11.0, 1H),3.56 (d, J=11.2, 1H), 3.15 (dd, J=8.0, 5.6, 1H), 3.00-2.66 (m, 2H), 2.12(m, 1H), 1.17 (d, J=6.8, 3H).

Example 780

5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine(Diastereoisomeric Mixture)

The title compound was prepared as described in Step C of Example 504utilizing a diastereoisomeric mixture of 2,6-dimethylmorpholine. MS(ESI): mass calcd. for C₂₃H₂₃FN₄O₂, 406.18; m/z found, 407.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=9.3, 2H), 7.68-7.59 (m, 1H),7.54-7.45 (m, 3H), 7.36-7.26 (m, 3H), 6.91 (d, J=10.5, 2H), 4.29 (d,J=12.6, 2H), 3.00 (dd, J=31.3, 12.7, 1H), 2.59-2.50 (m, 1H), 2.40-2.26(m, 1H), 2.17-2.07 (m, 1H), 1.12-0.96 (m, 3H), 0.89-0.72 (m, 3H).

Example 781

5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared as described in Example 376 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine.MS (ESI): mass calcd. for C₂₃H₁₉FN₄O₂, 402.15; m/z found, 403.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 8.73-8.64 (m, 1H), 8.55 (s, 1H),8.18 (m, 1H), 7.88-7.79 (m, 1H), 7.60 (m, 1H), 7.51-7.41 (m, 1H),7.43-7.32 (m, 3H), 6.65-6.55 (m, 1H), 3.73 (dd, J=5.8, 4.0, 2H), 3.63(dd, J=5.7, 4.2, 2H), 3.34 (dd, J=5.6, 4.1, 2H), 3.18-3.06 (m, 2H).

(3-Bromopyridin-2-yl)(morpholino)methanone

To a round-bottomed flask that had been purged with nitrogen, were added3-bromopicolinic acid (500 mg, 2.50 mmol), morpholine (259 mg, 3.00mmol), EDCI (712 mg, 3.70 mmol), HOBT (501 mg, 3.70 mmol), triethylamine(1.0 mL, 7.4 mmol) and DMF (12 mL). The mixture was stirred at rt for 24h, before diluting with water (100 mL) and extracting with ethyl acetate(2×100 mL). The combined organic extracts were washed with saturatedbicarbonate (1×50 mL), water (2×50 mL), dried with sodium sulfate, andconcentrated to dryness. The crude product was purified by FCC toprovide the title compound. MS (ESI): mass calcd. for C₁₀H₁₁BrN₂O₂,270.00; m/z found, 271.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (dd,J=4.7, 1.4, 1H), 7.93 (dd, J=8.2, 1.4, 1H), 7.23 (dd, J=8.2, 4.7, 1H),3.90-3.77 (m, 4H), 3.74-3.62 (m, 2H), 3.30-3.15 (m, 2H).

Example 782

5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine

The title compound was prepared as described in Example 376 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₂, 379.14; m/z found, 380.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.72-8.63 (m, 1H), 8.56 (d, J=1.4, 2H),7.85-7.75 (m, 1H), 7.53-7.42 (m, 2H), 7.39-7.28 (m, 2H), 5.17 (s, 2H),3.71 (dd, J=5.6, 3.8, 2H), 3.63 (dd, J=5.6, 3.8, 2H), 3.37 (dd, J=5.6,4.2, 2H), 3.18-3.06 (m, 2H).

Example 783

5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2-amine

The title compound was prepared as described in Example 376 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₂, 379.14; m/z found, 380.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.67 (dd, J=4.8, 1.6, 1H), 8.61 (m, 1H), 8.12(d, J=1.4, 1H), 8.06 (m, 1H), 7.81 (dd, J=7.9, 1.6, 1H), 7.44 (dd,J=7.9, 4.8, 1H), 7.38 (dd, J=8.1, 1.8, 1H), 7.32 (dd, J=12.1, 1.8, 1H),4.72 (s, 2H), 3.69 (dd, J=5.6, 3.9, 2H), 3.60 (dd, J=5.7, 4.1, 2H), 3.30(dd, J=5.6, 4.1, 2H), 3.07 (dd, J=5.5, 4.1, 2H).

Example 784

2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Step C of Example 504utilizing t-butylamine. MS (ESI): mass calcd. for C₂₂H₂₀F₄N₄O, 432.16;m/z found, 432.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.32 (m, 1H),8.06-8.00 (m, 2H), 7.92-7.88 (m, 1H), 7.83 (d, J=8.2, 1H), 7.68-7.65 (m,2H), 7.38-7.35 (m, 2H), 6.68 (s, 2H), 1.21 (s, 9H).

Example 785

2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Step C of Example 504utilizing (R)-2-aminopropan-1-ol. MS (ESI): mass calcd. forC₂₁H₁₈F₄N₄O₂, 434.14; m/z found, 434.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.38 (s, 1H), 8.29 (d, J=7.9, 1H), 8.05 (s, 1H), 7.97-7.84 (m, 2H),7.77 (s, 1H), 7.71 (d, J=7.9, 1H), 7.37 (d, J=9.4, 2H), 6.71 (s, 2H),4.70 (s, 1H), 3.93-3.78 (m, 1H), 3.25-3.15 (m, 2H), 1.00 (d, J=6.2, 3H).

Example 786

2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Step C of Example 504utilizing (S)-2-aminopropan-1-ol. MS (ESI): mass calcd. forC₂₁H₁₈F₄N₄O₂, 434.14; m/z found, 434.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.42-8.39 (m, 1H), 8.31 (d, J=8.1, 1H), 8.07 (d, J=1.5, 1H), 7.96-7.89(m, 2H), 7.79 (s, 1H), 7.74 (d, J=8.0, 1H), 7.41 (s, 1H), 7.38 (dd,J=4.5, 1.6, 1H), 6.74 (s, 2H), 4.72 (t, J=5.7, 1H), 3.92-3.83 (m, 1H),3.25-3.19 (m, 2H), 1.02 (d, J=6.7, 3H).

Example 787

2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide

The title compound was prepared as described in Step C of Example 504utilizing (R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₁H₁₅F₇N₄O, 472.11; m/z found, 472.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.11 (d, J=8.8, 1H), 8.41-8.35 (m, 1H), 8.04 (d, J=1.4, 1H), 7.94-7.90(m, 2H), 7.80-7.72 (m, 2H), 7.36-7.28 (m, 2H), 6.72 (s, 2H), 4.70-4.60(m, 1H), 1.22 (d, J=7.0, 3H).

Example 788

2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide

The title compound was prepared as described in Step C of Example 504utilizing (S)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₁H₁₅F₇N₄O, 472.11; m/z found, 472.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.10 (d, J=8.8, 1H), 8.48 (s, 2H), 7.94 (d, J=8.1, 1H), 7.80-7.72 (m,2H), 7.65-7.61 (m, 1H), 7.34-7.30 (m, 2H), 6.90 (s, 2H), 4.69-4.60 (m,1H), 1.22 (d, J=7.0, 3H).

Example 789

2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide

The title compound was prepared as described in Step C of Example 504utilizing (R)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₁H₁₅F₇N₄O, 472.11; m/z found, 472.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.10 (d, J=8.8, 1H), 8.48 (s, 2H), 7.93 (d, J=8.0, 1H), 7.81-7.71 (m,2H), 7.65-7.61 (m, 1H), 7.37-7.26 (m, 2H), 6.91 (s, 2H), 4.68-4.62 (m,1H), 1.22 (d, J=7.0, 3H).

Example 790

2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide

The title compound was prepared as described in Step C of Example 504utilizing (S)-1,1,1-trifluoropropan-2-amine. MS (ESI): mass calcd. forC₂₁H₁₅F₇N₄O, 472.11; m/z found, 472.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.13 (d, J=8.8, 1H), 8.43-8.35 (m, 1H), 8.06 (d, J=1.4, 1H), 7.96-7.91(m, 2H), 7.77 (d, J=8.8, 2H), 7.37-7.29 (m, 2H), 6.73 (s, 2H), 4.71-4.61(m, 1H), 1.23 (d, J=7.0, 3H).

Example 791

[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-(3-hydroxyazetidin-1-yl)methanone

The title compound was prepared as described in Step C of Example 504utilizing azetidin-3-. MS (ESI): mass calcd. for C₂₀H₁₇FN₄O₂, 364.13;m/z found, 364.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 2H),7.65-7.61 (m, 1H), 7.57-7.40 (m, 4H), 7.35-7.30 (m, 2H), 6.88 (s, 2H),5.65 (d, J=4.8, 1H), 4.31 (s, 1H), 4.11-4.04 (m, 1H), 3.81 (t, J=7.9,1H), 3.60 (dd, J=10.2, 4.4, 1H), 3.39 (dd, J=9.1, 4.4, 1H).

Example 792

[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[4-(methylamino)-1-piperidyl]methanone

The title compound was prepared as described in Step C of Example 504utilizing N-methylpiperidin-4-amine. MS (ESI): mass calcd. forC₂₃H₂₄FN₅O, 405.20; m/z found, 405.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.61 (d, J=10.6, 2H), 7.71-7.55 (m, 4H), 7.54-7.32 (m, 3H), 4.57 (d,J=12.6, 1H), 3.45-3.43 (m, 1H), 3.05-2.90 (m, 1H), 2.75-2.63 (m, 1H),2.59-2.54 (m, 1H), 2.35 (m, 3H), 2.02-1.92 (m, 1H), 1.73-1.62 (m, 1H),1.41-1.16 (m, 1H), 1.08-0.44 (m, 1H).

Example 793

[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The title compound was prepared as described in Step C of Example 504utilizing thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. forC₂₂H₁₈F₄N₄O₃S, 494.10; m/z found, 494.8 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.49 (s, 2H), 8.03 (s, 1H), 7.94 (d, J=8.2H, 1H), 7.80 (d,J=8.1, 1H), 7.72-7.68 (m, 1H), 7.40 (d, J=11.7, 1H), 7.34 (d, J=7.6,1H), 6.92 (s, 2H), 4.25-4.10 (m, 1H), 3.68-3.65 (m, 1H), 3.59-3.48 (m,1H), 3.26-3.11 (m, 3H), 3.03-2.92 (m, 1H), 2.42-2.28 (m, 1H).

Example 794

2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Step C of Example 504utilizing t-butyl amine. MS (ESI): mass calcd. for C₂₂H₂₀F₄N₄O, 432.16;m/z found, 432.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 2H), 8.04(s, 1H), 7.83 (d, J=8.0, 1H), 7.71-7.58 (m, 3H), 7.41-7.32 (m, 2H), 6.87(s, 2H), 1.22 (s, 9H).

Example 795

[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone

The title compound was prepared as described in Step C of Example 504utilizing piperidin-4-ol. MS (ESI): mass calcd. for C₂₃H₂₀F₄N₄O₂,460.15; m/z found, 460.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39-8.33(m, 1H), 8.03 (s, 1H), 7.98-7.91 (m, 1H), 7.86 (d, J=8.2, 1H), 7.75 (dd,J=8.1, 3.2, 1H), 7.70 (d, J=6.3, 1H), 7.40-7.32 (m, 2H), 6.72 (s, 2H),4.69-4.61 (m, 1H), 3.99-3.73 (m, 1H), 3.53-3.50 (m, 1H), 3.17-2.59 (m,3H), 1.66-1.34 (m, 2H), 1.17-0.45 (m, 2H).

Example 796

[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone

The title compound was prepared as described in Step C of Example 504utilizing piperidin-4-ol. MS (ESI): mass calcd. for C₂₃H₂₀F₄N₄O₂,460.15; m/z found, 460.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d,J=7.1, 2H), 7.89 (d, J=8.2, 1H), 7.83-7.65 (m, 3H), 7.48-7.33 (m, 2H),6.91 (s, 2H), 4.05-4.02 (m, 1H), 3.91-3.76 (m, 1H), 3.64-3.48 (m, 1H),3.23-3.18 (m, 1H), 3.05-2.63 (m, 2H), 1.72-1.40 (m, 2H), 1.20-0.97 (m,2H).

Example 797

2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tetrahydropyran-4-yl-benzamide

The title compound was prepared as described in Step C of Example 504utilizing tetrahydro-2H-pyran-4-amine. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₂, 392.16; m/z found, 392.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.47 (d, J=1.1, 2H), 8.24 (d, J=7.8, 1H), 7.61-7.49 (m, 2H), 7.48-7.41(m, 3H), 7.32-7.29 (m, 2H), 6.87 (s, 2H), 3.89-3.79 (m, 1H), 3.76-3.73(m, 2H), 3.34 (s, 2H), 1.64-1.61 (m, 2H), 1.41-1.29 (m, 2H).

Example 798

[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone

The title compound was prepared as described in Step C of Example 504utilizing morpholin-2-ylmethanol. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₃,408.16; m/z found, 408.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H),8.07 (s, 1H), 7.97-7.91 (m, 1H), 7.58-7.25 (m, 6H), 4.51-4.31 (m, 1H),3.95-3.56 (m, 1H), 3.55-3.43 (m, 2H), 3.40-3.33 (m, 1H), 3.26-2.96 (m,2H), 2.90-2.63 (m, 1H), 2.60-2.19 (m, 1H).

Example 799

racemic[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone

The title compound was prepared as described in Step C of Example 504utilizing racemic morpholin-2-ylmethanol. MS (ESI): mass calcd. forC₂₂H₂₁FN₄O₃, 408.16; m/z found, 409.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.52 (s, 2H), 7.67-7.25 (m, 7H), 4.49-4.33 (m, 1H), 3.96-3.56 (m, 1H),3.56-3.43 (m, 2H), 3.41-3.31 (m, 1H), 3.23-2.95 (m, 2H), 2.89-2.53 (m,1H), 2.52-2.13 (m, 1H).

N-(3-Bromopyridin-2-yl)pivalamide

3-Bromopyridin-2-amine (500 mg, 2.89 mmol) and pivaloyl chloride (420mg, 3.48 mmol) were added to a 50 mL round-bottomed flask. Pyridine (10mL) was then added and the mixture stirred and heated at 80° C. for 4 h.The reaction was then cooled to rt and stirred overnight. The reactionmixture was then concentrated to dryness and the resultant residuesubjected to FCC to provide the title compound. MS (ESI): mass calcd.for C₁₀H₁₃BrN₂O, 256.02; m/z found, 257.1 [M+H]⁺.

Example 800

N-{3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide

The title compound was prepared as described in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amineand N-(3-bromopyridin-2-yl)pivalamide. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O, 365.17; m/z found, 366.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 9.65 (s, 1H), 8.52-8.43 (m, 3H), 7.93-7.83 (m, 1H), 7.56-7.64 (m, 1H),7.47-7.68 (m, 1H), 7.38-7.26 (m, 2H), 6.93 (s, 2H), 1.05 (s, 9H).

Example 801

N-{3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide

The title compound was prepared as described in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrazin-2-amineand N-(3-bromopyridin-2-yl)pivalamide. MS (ESI): mass calcd. forC₂₀H₂₀FN₅O, 365.17; m/z found, 366.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.66 (s, 1H), 8.52-8.42 (m, 1H), 8.40-8.30 (m, 1H), 8.03 (d, J=1.4, 1H),7.95-7.82 (m, 2H), 7.47-7.38 (m, 1H), 7.39-7.30 (m, 1H), 6.73 (s, 2H),1.05 (s, 9H).

Example 802

N-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2-dimethylpropanamide

The title compound was prepared as described in Example 376 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand N-(3-bromopyridin-2-yl)pivalamide. MS (ESI): mass calcd. forC₂₃H₂₁FN₄O, 388.17; m/z found, 389.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.81 (s, 1H), 9.67 (s, 1H), 8.54-8.46 (m, 1H), 8.42-8.33 (m, 1H),8.18-8.09 (m, 1H), 7.96-7.87 (m, 1H), 7.71-7.62 (m, 1H), 7.55 (d, J=3.5,1H), 7.50-7.40 (m, 1H), 7.41-7.31 (m, 2H), 6.54 (d, J=3.5, 1H), 1.07 (s,9H).

Example 803

racemic5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrazin-2-aminehydrochloride Step A: 3-Bromopyridine-2-thiol

A mixture of 3-bromo-2-chloropyridine (10 g, 0.050 mol) and Na₂S (12 g,0.15 mol) in DMF (150 mL) was stirred at 120° C. for 16 h. and thereaction mixture was cooled to rt and then concentrated to dryness. Theresultant residue was diluted with water (80 mL), acidified to pH=5-6with conc. HCl, and then extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated todryness to give the title compound (6.4 g, crude). MS (ESI): mass calcd.For C₅H₄BrNS 188.92; m/z found, 191.9 [M+H]⁺.

Step B: tert-Butyl 3-(3-bromopyridin-2-ylthio)pyrrolidine-1-carboxylate

A mixture of 3-bromopyridine-2-thiol (0.30 g, 1.6 mmol), tert-butyl3-bromopyrrolidine-1-carboxylate (0.79 g, 3.2 mmol) and K₂CO₃ (438 mg,3.20 mmol) in DMF (12 mL) was stirred at rt for 4 h. The reactionmixture was concentrated to dryness and the residue subjected to FCCpurification to give partially purified title compound (1.05 g, 63%purity).

Step C: tert-Butyl3-(3-bromopyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl3-(3-bromopyridin-2-ylthio)pyrrolidine-1-carboxylate (0.9 g, 63% purity,1.6 mmol) in DCM/CH₃CN (20 mL/20 mL) were added NaIO₄ (1.6 g, 7.6 mmol),H₂O (20 mL), and RuCl₃ (10 mg, 0.070 mmol). The mixture was stirred atrt for 10 minutes and then concentrated to dryness. The resultantresidue was diluted with water (50 mL) and extracted with DCM (3×40 mL).The combined extracts were dried over MgSO₄, concentrated to dryness togive impure title compound (1.0 g, 60% purity) which was used for nextstep without any further purification.

Step D: tert-Butyl3-(3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl3-(3-bromopyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate (205 mg, 60%purity, 0.320 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(100 mg, 0.320 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (23 mg, 0.030 mmol), and Na₂CO₃(101 mg, 0.950 mmol) in DMF (6 mL) was stirred at 100° C. for 16 h underN₂ before cooling to rt and concentrating it to dryness. The resultantresidue was subjected to FCC followed by HPLC purification to give thetitle compound (150 mg, 99%). MS (ESI): mass calcd. For C₂₄H₂₆FN₅O₄S499.17; m/z found, 521.9 [M+Na]⁺.

Step E:5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrazin-2-aminehydrochloride

To a solution consisting of tert-butyl3-(3-(4-(5-aminopyrazin-2-yl)-3-fluorophenyl)pyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate(150 mg, 0.300 mmol) and DCM (10 mL) was added HCl/EtOH (5 N, 10 mL).The mixture was stirred at rt for 2 h, concentrated to dryness, and theresultant residue subjected to HPLC purification to give the titlecompound (67 mg, 52%). MS (ESI): mass calcd. For C₁₉H₁₈FN₅O₂S.HCl399.12; m/z found, 400.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (br s,1H), 9.42 (br s, 1H), 8.79 (d, J=4.6, 1H), 8.51-8.30 (m, 1H), 8.20-7.78(m, 3H), 7.51-7.02 (m, 3H), 4.81 (dd, J=14.1, 7.6, 1H), 3.72 (s, 1H),3.49-3.14 (m, 3H), 2.44-2.20 (m, 2H).

Example 804

5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step E of Example 803using tert-butyl3-(3-(4-(5-aminopyrimidin-2-yl)-3-fluorophenyl)pyridin-2-ylsulfonyl)pyrrolidine-1-carboxylate.MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂S, 399.12; m/z found, 400.1 [M+H]⁺.¹H NMR (300 MHz, CD₃OD) δ 8.71 (dd, J=4.7, 1.6, 1H), 8.52 (d, J=1.4,2H), 8.41 (br s, 1H), 8.03 (dd, J=7.9, 1.5, 1H), 7.78 (dd, J=7.9, 4.7,1H), 7.58 (m, 1H), 7.49-7.35 (m, 2H), 4.95-4.90 (m, 1H), 3.81 (dd,J=13.3, 8.9, 1H), 3.66 (dd, J=13.3, 5.4, 1H), 3.44-3.33 (m, 2H),2.52-2.38 (m, 2H).

Example 805

5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclobutylsulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-.MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₂S.HCl, 384.11; m/z found, 385.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, J=0.8, 2H), 8.70 (dd, J=4.7,1.6, 1H), 7.99 (dd, J=7.8, 1.6, 1H), 7.74 (dd, J=7.8, 4.7, 1H), 7.69 (m,1H), 7.53-7.46 (m, 2H), 4.80-4.69 (m, 1H), 2.54-2.41 (m, 2H), 2.41-2.30(m, 2H), 2.20-2.07 (m, 1H), 2.05-1.94 (m, 1H).

Example 806

5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclobutylsulfonyl)pyridine. MS (ESI): mass calcd. forC₁₉H₁₇FN₄O₂S.HCl, 384.11; m/z found, 385.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.69 (dd, J=4.7, 1.5, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.12 (m,1H), 7.99 (dd, J=7.8, 1.5, 1H), 7.74 (dd, J=7.8, 4.7, 1H), 7.49 (d,J=2.7, 1H), 7.46 (s, 1H), 4.80-4.70 (m, 1H), 2.54-2.42 (m, 2H),2.40-2.30 (m, 2H), 2.21-2.07 (m, 1H), 2.04-1.94 (m, 1H).

Example 807

5-(4-(2-(Cyclohexlsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclohexylsulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂S.HCl, 412.14; m/z found, 413.1[M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.74 (dd, J=4.6, 1.6, 1H), 8.56 (s,2H), 7.96 (dd, J=7.9, 1.6, 1H), 7.74 (dd, J=7.9, 4.7, 1H), 7.57 (m, 1H),7.37 (dd, J=3.6, 1.3, 1H), 7.34 (s, 1H), 3.97-3.83 (m, 1H), 2.01-1.63(m, 5H), 1.52-1.13 (m, 5H).

Example 808

5-(4-(2-(Cyclohexylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclohexylsulfonyl)pyridine. MS (ESI): mass calcd. forC₂₁H₂₁FN₄O₂S.HCl, 412.14; m/z found, 413.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.78 (d, J=4.4, 1H), 8.39 (s, 1H), 8.02 (d, J=6.3, 2H), 7.90(m, 1H), 7.80 (dd, J=7.8, 4.6, 1H), 7.35 (dd, J=14.8, 10.8, 2H), 6.75(s, 2H), 3.98-3.80 (m, 1H), 1.80 (d, J=14.9, 4H), 1.62 (d, J=12.3, 1H),1.39-1.07 (m, 5H).

Example 809

5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidine-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclopentylsulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₂S.HCl, 398.12; m/z found, 399.1[M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.88 (s, 2H), 8.73 (dd, J=4.6, 1.5,1H), 7.96 (dd, J=7.8, 1.5, 1H), 7.80-7.62 (m, 2H), 7.55-7.41 (m, 2H),4.56-4.40 (m, 1H), 2.09-1.79 (m, 4H), 1.69 (d, J=4.7, 4H).

Example 810

5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(cyclopentylsulfonyl)pyridine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₂S.HCl, 398.12; m/z found, 399.10 [M+H]⁺. ¹H NMR (300 MHz,CD₃OD) δ 8.80-8.68 (m, 2H), 8.25 (d, J=1.1, 1H), 8.13 (m, 1H), 7.96 (dd,J=7.8, 1.5, 1H), 7.73 (dd, J=7.8, 4.6, 1H), 7.43 (d, J=10.3, 2H),4.52-4.39 (m, 1H), 2.10-1.80 (m, 4H), 1.68 (d, J=5.4, 4H).

Example 811

5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(tert-butylsulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.0 [M+H]⁺.¹H NMR (300 MHz, CDCl₃) δ 8.73 (dd, J=4.6, 1.7, 1H), 8.56 (d, J=1.4,2H), 7.73 (dd, J=7.8, 1.7, 1H), 7.56 (dd, J=7.8, 4.6, 1H), 7.41 (m, 1H),7.28 (dd, J=7.9, 1.8, 1H), 7.21 (d, J=1.7, 1H), 5.29 (s, 2H), 1.48 (s,9H).

Example 812

5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(tert-butylsulfonyl)pyridine. MS (ESI): mass calcd. forC₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.0 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ8.73 (dd, J=4.5, 1.7, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.98 (m, 1H),7.74 (dd, J=7.8, 1.7, 1H), 7.56 (dd, J=7.8, 4.6, 1H), 7.28 (d, J=1.7,1H), 7.20 (d, J=1.7, 1H), 5.01 (s, 2H), 1.45 (s, 9H).

Example 813

racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformate

The title compound was prepared as described in step D of Example 803using racemic 3-bromo-2-(sec-butylsulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.0 [M+H]⁺.¹H NMR (300 MHz, CD₃OD) δ 8.73 (dd, J=4.6, 1.6, 1H), 8.53 (d, J=1.4,2H), 7.96 (dd, J=7.8, 1.6, 1H), 7.73 (dd, J=7.8, 4.6, 1H), 7.56 (m, 1H),7.40-7.32 (m, 2H), 4.00-3.89 (m, 1H), 1.95-1.81 (m, 1H), 1.53-1.43 (m,1H), 1.23 (d, J=8.3, 3H), 1.01 (t, J=7.5, 3H).

Example 814

racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformate

The title compound was prepared as described in step D of Example 803using racemic 3-bromo-2-(sec-butylsulfonyl)pyridine. MS (ESI): masscalcd. for C₁₉H₁₉FN₄O₂S, 386.12; m/z found, 387.0 [M+H]⁺. ¹H NMR (300MHz, CD₃OD) δ 8.73 (dd, J=4.6, 1.6, 1H), 8.41-8.35 (m, 1H), 8.20 (d,J=1.4, 1H), 8.03-7.94 (m, 2H), 7.74 (dd, J=7.8, 4.6, 1H), 7.40-7.32 (m,2H), 3.90 (s, 1H), 1.92-1.82 (m, 1H), 1.53-1.42 (m, 1H), 1.24 (d, J=6.9,3H), 1.00 (t, J=7.5, 3H).

Example 815

1-((3-(4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanone

The title compound was prepared as described in step D of Example 803using 1-(4-((3-bromopyridin-2-yl)sulfonyl)piperidin-1-yl)ethanone and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₂H₂₂FN₅O₃S.HCl, 455.14; m/z found, 456.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.76 (dd, J=4.6, 1.6, 1H), 8.56 (d,J=1.3, 2H), 8.00 (dd, J=7.9, 1.6, 1H), 7.78 (dd, J=7.9, 4.7, 1H), 7.59(m, 1H), 7.40 (dd, J=4.3, 1.4, 1H), 7.38 (s, 1H), 4.61 (d, J=13.4, 1H),4.35 (m, 1H), 4.06 (d, J=14.0, 1H), 3.24 (d, J=13.0, 2.8, 1H), 2.76 (m,1H), 2.11 (s, 3H), 2.09-1.97 (m, 2H), 1.74 (m, 1H), 1.61 (m, 1H).

Example 816

1-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanonehydrogen chloride salt

The title compound was prepared as described in step D of Example 803using 1-(4-((3-bromopyridin-2-yl)sulfonyl)piperidin-1-yl)ethanone. MS(ESI): mass calcd. for C₂₂H₂₂FN₅O₃S.HCl, 455.14; m/z found, 456.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.76 (dd, J=4.6, 1.6, 1H), 8.46-8.39(m, 1H), 8.10 (d, J=1.4, 1H), 8.01 (dd, J=7.9, 1.6, 1H), 7.96 (m, 1H),7.78 (dd, J=7.9, 4.7, 1H), 7.39 (s, 1H), 7.37 (dd, J=4.4, 1.5, 1H), 4.60(d, J=13.5, 1H), 4.37-4.26 (m, 1H), 4.05 (d, J=14.0, 1H), 3.23 (m, 1H),2.75 (m, 1H), 2.10 (s, 3H), 2.07-1.97 (m, 2H), 1.74 (m, 1H), 1.61 (m,1H).

Example 817

5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-aminehydrogen chloride salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-((3-methoxypropyl)sulfonyl)pyridine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.74 (dd, J=4.6, 1.5, 1H), 8.61 (s, 2H), 7.99(dd, J=7.8, 1.5, 1H), 7.76 (dd, J=7.8, 4.7, 1H), 7.60 (m, 1H), 7.42 (dd,J=3.9, 1.3, 1H), 7.40 (s, 1H), 3.70-3.62 (m, 2H), 3.48 (m, 2H), 3.32 (s,3H), 2.03-1.94 (m, 2H).

Example 818

5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-aminehydrogen chloride salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-((3-methoxypropyl)sulfonyl)pyridine. MS (ESI): masscalcd. for C₁₉H₁₉FN₄O₃S, 402.12; m/z found, 403.1 [M+H]⁺. ¹H NMR (300MHz, CD₃OD) δ 8.69 (d, J=3.5, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.04-7.90(m, 2H), 7.72 (dd, J=7.8, 4.7, 1H), 7.39 (s, 1H), 7.35 (d, J=2.0, 1H),3.68-3.56 (m, 2H), 3.45 (m, 2H), 3.29 (s, 3H), 2.04-1.89 (m, 2H).

Example 819

4-((3-(4-(2-aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide

The title compound was prepared as described in step D of Example 803using 4-((3-bromopyridin-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-aminegiving the target molecule after purification by HPLC. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₄S₂.HCOOH, 462.08; m/z found, 463.00 [M+H]⁺. ¹H NMR(300 MHz, CDCl₃) δ 8.67 (d, J=4.1, 1H), 8.58 (s, 2H), 7.87 (d, J=7.3,1H), 7.72-7.59 (m, 1H), 7.56-7.44 (m, 1H), 7.42-7.29 (d, J=14.6, 2H),5.22 (s, 2H), 4.52-4.48 (m, 1H), 3.43-3.23 (m, 2H), 3.03 (s, 2H),2.68-2.47 (m, 4H).

Example 820

4-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide

The title compound was prepared as described in step D of Example 803using 4-((3-bromopyridin-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide giving the target molecule after purification by HPLC. MS(ESI): mass calcd. for C₂₀H₁₉FN₄O₄S₂.HCOOH, 462.08; m/z found, 463.00[M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 8.66 (dd, J=4.6, 1.6, 1H), 8.63-8.59(m, 1H), 8.11 (d, J=1.5, 1H), 8.06 (m, 1H), 7.86 (dd, J=7.8, 1.6, 1H),7.63 (dd, J=7.8, 4.6, 1H), 7.37 (dd, J=8.1, 1.8, 1H), 7.31 (dd, J=11.6,1.7, 1H), 4.77 (s, 2H), 4.42-4.28 (m, 1H), 3.45-3.27 (m, 2H), 3.10-2.94(m, 2H), 2.67-2.48 (m, 4H).

Example 821

5-(2-Fluoro-4-(2-((2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using 4-(2-((3-bromopyridin-2-yl)sulfonyl)ethyl)morpholine and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₁H₂₂FN₅O₃S.HCOOH, 443.14; m/z found, 444.10[M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 8.65 (dd, J=4.7, 1.6, 1H), 8.56 (s,2H), 7.82 (dd, J=7.8, 1.6, 1H), 7.61 (dd, J=7.9, 4.7, 1H), 7.47 (m, 1H),7.39 (dd, J=8.0, 1.7, 1H), 7.33 (dd, J=11.0, 1.7, 1H), 5.52 (s, 2H),3.85 (t, J=9, 2H), 3.63 (s, 4H), 2.93 (t, J=9, 2H), 2.54 (s, 4H).

Example 822

5-(2-Fluoro-4-(2-((2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-amine

The title compound was prepared as described in step D of Example 803using 4-(2-((3-bromopyridin-2-yl)sulfonyl)ethyl)morpholine giving thetarget molecule after purification by HPLC. MS (ESI): mass calcd. forC₂₁H₂₂FN₅O₃S.HCOOH, 443.14; m/z found, 444.10 [M+H]⁺. ¹H NMR (300 MHz,CDCl₃): δ 8.65 (dd, J=4.6, 1.6, 1H), 8.51 (s, 1H), 8.14 (d, J=1.5, 1H),8.04 (m, 1H), 7.83 (dd, J=7.8, 1.6, 1H), 7.61 (dd, J=7.8, 4.7, 1H),7.43-7.30 (m, 2H), 5.28 (m, 2H), 3.98-3.84 (m, 2H), 3.80-3.58 (m, 4H),3.09-2.96 (m, 2H), 2.78-2.54 (m, 4H).

Example 823

5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine. MS(ESI): mass calcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹HNMR (300 MHz, CD₃OD) δ 8.71 (dd, J=4.6, 1.5, 1H), 8.53 (d, J=1.3, 2 H),7.97 (dd, J=7.8, 1.6, 1H), 7.74 (dd, J=7.9, 4.6, 1H), 7.57 (m, 1H),7.44-7.35 (m, 2H), 3.96-3.78 (m, 2H), 3.57 (d, J=6.3, 2H), 3.47-3.37 (m,2H), 2.25-2.10 (m, 1H), 1.85-1.69 (m, 2H), 1.54-1.36 (m, 2H).

Example 824

5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrazin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using 3-bromo-2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine. MS(ESI): mass calcd. for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹HNMR (300 MHz, CDCl₃) δ 8.65 (dd, J=4.6, 1.6, 1H), 8.60 (s, 1H), 8.10 (s,1H), 8.04 (m, 1H), 7.82 (dd, J=7.8, 1.6, 1H), 7.59 (dd, J=7.8, 4.7, 1H),7.40 (dd, J=8.0, 1.7, 1H), 7.34 (dd, J=11.8, 1.6, 1H), 4.76 (s, 2H),3.92 (dd, J=10.6, 3.2, 2H), 3.56 (d, J=6.4, 2H), 3.39 (m, 2H), 2.40-2.26(m, 1H), 1.84 (d, J=11.0, 2H), 1.49 (m, 2H).

Example 825

5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. forC₁₈H₁₇FN₄O₂S, 372.11; m/z found, 373.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.69 (dd, J=4.7, 1.7, 1H), 8.57 (d, J=1.4, 2H), 7.80 (dd, J=7.8, 1.6,1H), 7.59 (dd, J=7.8, 4.6, 1H), 7.46 (m, 1H), 7.39 (dd, J=7.9, 1.8, 1H),7.32 (dd, J=11.1, 1.7, 1H), 5.17 (s, 2H), 4.26 (hept, J=6.9, 1H), 1.32(d, J=6.9, 6H).

Example 826

5-(2-Fluoro-4-(2-(isopropylsulfonyl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridineand 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. forC₂₁H₁₈FN₄O₂S, 395.11; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.45 (s, 1H), 8.70 (dd, J=4.6, 1.6, 2H), 8.25-8.17 (m, 1H), 7.84 (dd,J=7.8, 1.7, 1H), 7.64-7.54 (m, 2H), 7.46-7.32 (m, 3H), 6.61 (s, 1H),4.26 (hept, J=6.8, 1H), 1.34 (d, J=6.9, 6H).

Example 827

5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amine.MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.1 [M+H]⁺.¹H NMR (300 MHz, CDCl₃) δ 8.91 (s, 2H), 8.78 (m, 1H), 8.03 (m, 1H), 7.82(m, 1H), 7.75-7.71 (m, 1H), 7.50-7.42 (m, 2H), 4.52-4.46 (m, 1H),3.57-3.54 (m, 2H), 3.24-3.17 (m, 2H), 2.31-2.28 (m, 2H), 2.13-1.96 (m,2H).

Example 828

5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amineformic acid salt Step A: 3-Bromo-2-((3-chloropropyl)thio)pyridine

A mixture of 3-bromopyridine-2-thiol (0.04 g, 0.2 mmol),1-bromo-3-chloropropane in DMF (0.424 mmol/mL, 2.0 mL), and K₂CO₃ (60mg, 0.424 mmol) in DMF (2.0 mL) was stirred at rt for 10 minutes. Thereaction mixture was then concentrated to dryness and the resultantresidue diluted with water (10 mL) and extracted with ethyl acetate(3×10 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated to dryness to give the title compound (0.05 g, 89% purity).MS (ESI): mass calcd. for C₈H₉BrClNS, 264.93; m/z found, 265.8 [M+H]⁺.

Step B: 3-Bromo-2-((3-chloropropyl)sulfonyl)pyridine

To a solution of 3-bromo-2-((3-chloropropyl)thio)pyridine (0.05 g, 89%purity, 0.2 mmol) in DCM/CH₃CN (3.0 mL/3.0 mL) were added NaIO₄ (0.121g, 0.567 mmol), H₂O (3.0 mL), and RuCl₃ (2.0 mg, 0.014 mmol). Themixture was stirred at rt. for 10 minutes and concentrated to dryness.The residue was diluted with water (10 mL) and extracted with ethylacetate (3×10 mL). The combined organic extracts were dried over MgSO₄,and concentrated to dryness to give the title compound (0.05 g, 89%purity), which was used in next step without any further purification.MS (ESI): mass calcd. for C₈H₉BrClNO₂S, 296.92; m/z found, 297.9 [M+H]⁺.

Step C: 3-Bromo-2-(cyclopropylsulfonyl)pyridine

To a solution of 3-bromo-2-((chloropropyl)sulfonyl)pyridine (0.05 g, 89%purity, 0.2 mmol) in THF (20 mL) was added t-BuOK (0.047 g, 0.42 mmol)at −38° C. and the mixture was stirred for an additional 30 minutes. Thereaction was quenched by adding saturated NH₄Cl aqueous solution (2.5mL) and concentrated to dryness. The resultant residue was diluted withwater (10 mL) and extracted with DCM (2×10 mL). The combined organicextracts were dried over MgSO₄, and concentrated to dryness to give thetitle compound (0.08 g, crude), which was used in the next step withoutfurther purification. MS (ESI): mass calcd. for C₈H₈BrNO₂S, 260.95; m/zfound, 262.0 [M+H]⁺.

Step D:5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amineand 3-bromo-2-(cyclopropylsulfonyl). MS (ESI): mass calcd. forC₁₈H₁₅FN₄O₂S.HCOOH, 370.09; m/z found, 370.9 [M+H]⁺. ¹H NMR (300 MHz,CDCl₃) δ 8.67 (m, 1H), 8.55 (s, 2H), 7.76 (m, 1H), 7.55 (m, 1H),7.49-7.27 (m, 3H), 5.37 (s, 2H), 3.23-3.08 (m, 1H), 1.25-1.01 (m, 4H).

Example 829

5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrazin-2-amineand 3-bromo-2-(cyclopropylsulfonyl)pyridine. MS (ESI): mass calcd. forC₁₈H₁₅FN₄O₂S, 370.09; m/z found, 370.9 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ8.66 (m, 1H), 8.55 (s, 1H), 8.06 (d, J=1.4, 1H), 8.02-7.96 (m, 1H), 7.77(m, 1H), 7.54 (m, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 4.70 (s, 2H),3.12-3.01 (m, 1H), 1.25-0.97 (m, 4H).

Example 830

5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrazin-2-amineand 3-bromo-2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyridine. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₃S.HCl, 414.12; m/z found, 415.1 [M+H]⁺; ¹HNMR (300 MHz, CDCl₃) δ 8.78 (d, J=4.6, 1H), 8.40 (s, 1H), 8.13-7.99 (m,2H), 7.95-7.89 (m, 1H), 7.87-7.78 (m, 1H), 7.38 (m, 2H), 6.76 (s, 2H),4.33-4.20 (m, 1H), 3.92 (dd, J=11.1, 3.7, 2H), 3.50-3.35 (m, 2H),1.85-1.69 (m, 2H), 1.69-1.48 (m, 2H).

Example 831

5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amineformic acid salt

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrimidin-2-amineand 3-bromo-2-((tetrahydro-2H-pyran-4-yl)sulfonyl)pyridine. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.1 [M+H]⁺; ¹H NMR(300 MHz, CD₃OD) δ 8.78 (m, 1H), 8.52 (d, J=1.4, 2H), 8.04 (m, 1H), 7.82(m, 1H), 7.67-7.61 (m, 1H), 7.43 (m, 1H), 7.36 (m, 1H), 6.95 (s, 2H),4.29-4.24 (m, 1H), 3.94-3.89 (m, 2H), 3.45-3.35 (m, 2H), 1.77-1.73 (m,2H), 1.77-1.52 (m, 2H).

Example 832

5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride

The title compound was prepared as described in step D of Example 803using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenyl)pyrazin-2-amine.MS (ESI): mass calcd. for C₂₀H₂₀FN₅O₂S, 413.13; m/z found, 414.1 [M+H]⁺.¹H NMR (300 MHz, CD₃OD) δ 8.81-8.69 (m, 1H), 8.54 (s, 1H), 8.29 (s, 1H),8.11-8.06 (m, 1H), 8.01 (m, 1H), 7.78 (m, 1H), 7.42 (s, 1H), 7.39 (d,J=2.1, 1H), 4.55-4.38 (m, 1H), 3.54-3.50 (m, 2H), 3.19-3.12 (m, 2H),2.30-2.26 (m, 2H), 2.09-1.88 (m, 2H).

Example 833

5-(2,3-Difluorobiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared by a method analogous to Example 461using phenylboronic acid. MS (ESI): mass calcd. for C₁₆H₁₁F₂N₃, 283.09;m/z found, 284.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.43-8.40 (m, 1H),8.04 (d, J=1.5, 1H), 7.78-7.72 (m, 1H), 7.65-7.60 (m, 2H), 7.55-7.50 (m,2H), 7.50-7.41 (m, 2H), 6.83 (s, 2H).

5-(4-Bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine Step A:(4-Bromo-2-fluoro-3-methoxyphenyl)boronic acid

A solution of 2,2′,6,6′-tetramethylpiperidine (0.98 ml, 5.8 mmol) in THF(9.8 ml) was cooled to −78° C. under a N₂ atmosphere. To the solutionwas then added n-BuLi (2.21 N in hexanes, 2.45 ml, 5.41 mmol) drop-wiseover a couple of minutes, and then the mixture warmed to 0° C. for 20-30min. The mixture was then cooled back to −78° Celsius and treated withtriisopropyl borate (1.25 ml, 5.41 mmol). After 5minutesl-bromo-3-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) was slowlyadded and the reaction stirred at −78° Celsius for 1.5 h before warmingto rt The reaction mixture was then treated with AcOH (2.8 ml, 49 mmol),diluted with water, and extracted with EtOAc. The EtOAc extract wasdried over MgSO₄, filtered, and concentrated to dryness. The crudeproduct was used without purification.

Step B: 5-(4-Bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

A mixture of (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid (940 mg,1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) was treatedwith EtOH (12.4 ml), toluene (12.8 ml), and aqueous Na₂CO₃ (2.0 N, 9.44ml, 18.9 mmol), and the resulting mixture deoxygenated by sparging withfor 10 minutes. Pd(PPh₃)₄ (218 mg, 0.189 mmol) was then added, and themixture heated at 80° Celsius for 17 h. The reaction was cooled to rtand then partitioned between saturated aqueous NH₄Cl and EtOAc. Theorganic layer was isolated, dried over MgSO₄, and concentrated todryness. The resultant residue was suspended in DCM and the titlecompound isolated by filtration (300 mg, 27%), which was used withoutfurther purification. Additional product was obtained by concentratingthe filtrate to dryness and subjecting the residue to FCC (560 mg, 50%).MS (ESI): mass calcd. for C₁₁HgBrFN₃O, 296.99; m/z found, 298.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.00 (d, J=1.5,1H), 7.54-7.49 (m, 2H), 6.78 (s, 2H), 3.90 (d, J=0.6, 3H).

Example 834

5-(3-Fluoro-2-methoxybiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared by a method analogous to Example 461using phenylboronic acid and5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): masscalcd. for C₁₇H₁₄FN₃O, 295.11; m/z found, 296.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.58-8.55 (m, 1H), 8.12 (d, J=1.5, 1H), 7.65 (dd, J=8.1, 7.5,1H), 7.61-7.54 (m, 2H), 7.48-7.42 (m, 2H), 7.41-7.34 (m, 1H), 7.23 (dd,J=8.2, 1.4, 1H), 4.69 (s, 2H), 3.74 (d, J=0.9, 3H).

Example 835

5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared by a method analogous to Example 461using 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI):mass calcd. for C₁₈H₁₆FN₃O₃S, 373.09; m/z found, 374.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 8.58-8.53 (m, 1H), 8.21 (dd, J=8.0, 1.3, 1H), 8.11(d, J=1.5, 1H), 7.71-7.58 (m, 3H), 7.35 (dd, J=7.5, 1.2, 1H), 7.13 (dd,J=8.1, 1.3, 1H), 4.74 (s, 2H), 3.82 (d, J=1.9, 3H), 2.96 (s, 3H).

Example 836

4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2′-methoxybiphenyl-2-sulfonamide

The title compound was prepared by a method analogous to Example 461using (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid and5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): masscalcd. for C₂₁H₂₃FN₄O₃S, 430.15; m/z found, 431.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.53-8.48 (m, 1H), 8.19 (dd, J=7.9, 1.4, 1H), 8.08 (d,J=1.5, 1H), 7.64-7.55 (m, 2H), 7.52 (m, 1H), 7.29 (dd, J=7.4, 1.4, 1H),7.18 (dd, J=8.2, 1.4, 1H), 4.80 (s, 2H), 4.42 (s, 1H), 3.85 (d, J=1.8,3H), 1.21 (s, 9H).

Example 837

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide

The title compound was prepared by a method analogous to Example 461using (2-(methylsulfonamido)phenyl)boronic acid and5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): masscalcd. for C₁₈H₁₇FN₄O₃S, 388.10; m/z found, 389.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.59 (dd, J=2.3, 1.6, 1H), 8.12 (d, J=1.5, 1H), 7.75 (dd,J=8.2, 7.2, 1H), 7.69 (d, J=8.0, 1H), 7.46 (m, 1H), 7.37-7.32 (m, 2H),7.15 (dd, J=8.2, 1.5, 1H), 7.10 (s, 1H), 4.77 (s, 2H), 3.73 (d, J=1.1,3H), 2.58 (s, 3H).

Example 838

5-(3-Fluoro-2′-(pyrazin-2-yl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine StepA: 2-(2-Chlorophenyl)pyrazine

2-Bromopyrazine (100 mg, 0.630 mmol) and ((2-chlorophenyl)boronic acid(103 mg, 0.660 mmol) were added to a 5 mL sealable vial equipped with astir-bar. A solution consisting of 1,4-dioxane (3 mL) and Na₂CO₃ (1.6mL, 2 M) was added and the mixture sparged with argon for 10 minutesbefore adding Pd(ddp)Cl₂.CH₂Cl₂ (23 mg, 0.031 mmol) and heating at 80°Celsius for 15 hours. The reaction was then cooled to rt, diluted with 5mL of ethyl acetate and 5 mL of water, and the mixture extracted withethyl acetate (3×20 mL). The combined organic extracts were then driedwith sodium sulfate and concentrated to dryness. The resultant residuewas subjected to FCC to provide the title compound. ¹H NMR (500 MHz,CDCl₃) δ 8.98-8.96 (d, J=1.6, 1H), 8.70-8.68 (dd, J=2.5, 1.6, 1H),8.58-8.56 (d, J=2.6, 1H), 7.66-7.58 (m, 1H), 7.54-7.50 (m, 1H),7.43-7.39 (m, 2H).

Step B: 5-(3-Fluoro-2′-pyrazin-2-ylbiphenyl-4-yl)pyrazin-2-amine

2-(2-Chlorophenyl)pyrazine (58 mg, 0.31 mmol),5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine(88 mg, 0.28 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.4 mg, 0.0060 mmol) were placed into a sealable 5 mL vial equippedwith a stir-bar. The vial was sealed, evacuated and backfilled withargon three times. To this vial was added separately deoxygenated THF(0.56 mL) and K₃PO₄ (1.1 mL, 0.5 M). The vial was then heated at 45°Celsius for 1 hour before cooling to rt diluting with brine (5 mL), andextracting with EtOAc (1×5 mL, 3×10 mL). The combined organic extractswere then dried with sodium sulfate, filtered, and concentrated todryness. The crude product was purified via FCC to provide the titlecompound. MS (ESI): mass calcd. for C₂₀H₁₄FN₅, 343.12; m/z found, 344.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.65-8.59 (dd, J=2.6, 1.6, 1H),8.47-8.42 (d, J=2.6, 1H), 8.33-8.31 (dd, J=2.2, 1.4, 1H), 8.31-8.29 (d,J=1.5, 1H), 8.04-8.02 (d, J=1.5, 1H), 7.79-7.73 (m, 1H), 7.72-7.69 (m,1H), 7.64-7.53 (m, 3H), 7.11-6.87 (m, 2H).

Example 839

5-(3-Fluoro-2′-pyrazin-2-ylbiphenyl-4-yl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-aminein Step B. MS (ESI): mass calcd. for C₂₀H₁₄FN₅, 343.12; m/z found, 344.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.61 (s, 1H), 8.56 (s, 2H), 8.47-8.40(d, J=2.6, 1H), 8.31 (s, 1H), 7.74-7.67 (d, J=7.3, 1H), 7.65-7.57 (m,1H), 7.57-7.54 (d, J=7.3, 1H), 7.46-7.41 (m, 1H), 7.08-7.04 (d, J=11.8,1H), 7.04-7.00 (d, J=8.0, 1H).

Example 840

5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 847 using 5-bromopyrazin-2-amine in Step A. MS (ESI): masscalcd. for C₂₀H₁₅FN₆, 358.13; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.37-8.29 (m, 1H), 8.06-8.02 (d, J=1.5, 1H), 7.93-7.90 (d,J=1.5, 1H), 7.82-7.73 (m, 1H), 7.63-7.55 (m, 2H), 7.53-7.44 (m, 3H),7.05-6.97 (m, 2H).

Example 841

5-[2′-(5-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromopyrazin-2-amine in Step A and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-aminein Step B. MS (ESI): mass calcd. for C₂₀H₁₅FN₆, 358.13; m/z found, 359.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.50-8.44 (d, J=1.4, 2H), 7.95-7.90(d, J=1.5, 1H), 7.63-7.55 (m, 2H), 7.52-7.44 (m, 3H), 7.43-7.38 (m, 1H),7.06-7.03 (m, 1H), 7.03-7.01 (dd, J=6.2, 1.6, 1H).

Example 842

5-[2′-(6-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 6-bromopyrazin-2-amine in Step A. MS (ESI): masscalcd. for C₂₀H₁₅FN₆, 358.13; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.34-8.25 (m, 1H), 8.15-8.08 (d, J=1.5, 1H), 7.86-7.78 (m, 1H),7.77 (s, 1H), 7.66-7.59 (m, 1H), 7.59-7.48 (m, 3H), 7.40 (s, 1H),7.10-7.00 (m, 2H).

Example 843

5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromopyrimidin-2-amine in Step A. MS (ESI): masscalcd. for C₂₀H₁₅FN₆, 358.13; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.33 (s, 1H), 8.19-8.14 (m, 2H), 8.12-8.08 (d, J=1.9, 1H),7.90-7.80 (dd, J=8.8, 7.2, 1H), 7.57-7.41 (m, 4H), 7.12 (s, 1H), 7.10(s, 1H).

Example 844

5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromopyrimidin-2-amine in Step A and5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-aminein Step B. MS (ESI): mass calcd. for C₂₀H₁₅FN₆, 358.13; m/z found, 359.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.57 (s, 2H), 8.16 (d, J=2.0, 2H),7.57-7.45 (m, 5H), 7.14 (t, J=10.3, 2H).

Example 845

5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-bromo-1-chloro-4-(trifluoromethyl)benzene in Step A and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine in StepB. MS (ESI): mass calcd. for C₂₁H₁₄F₄N₆, 426.12; m/z found, 427.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.36 (dd, J=2.1, 1.5, 1H), 8.10 (s,2H), 8.05 (d, J=1.5, 1H), 7.90-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.74 (d,J=1.8, 1H), 7.66 (d, J=8.0, 1H), 7.13 (dd, J=2.6, 1.7, 1H), 7.11 (dd,J=6.5, 1.6, 1H).

Example 846

5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromo-2-methoxypyrimidine in Step A. MS (ESI): masscalcd. for C₂₁H₁₆FN₅O, 373.13; m/z found, 374.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.36 (s, 2H), 8.34 (dd, J=2.1, 1.4, 1H), 8.04 (d, J=1.5, 1H),7.84-7.74 (m, 1H), 7.56-7.44 (m, 4H), 7.12-6.97 (m, 2H), 3.98 (s, 3H).

Example 847

5-[3-Fluoro-2′-(1-methyl-1H-pyrazol-4-yl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 4-bromo-1-methyl-1H-pyrazole in Step A. MS (ESI): masscalcd. for C₂₀H₁₆FN₅, 345.14; m/z found, 346.2 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.38-8.35 (m, 1H), 8.06 (d, J=1.5, 1H), 7.85-7.79 (m, 1H),7.51-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.37-7.32 (m, 3H), 7.15-7.11 (m,2H), 7.05 (dd, J=12.2, 1.7, 1H), 3.80 (s, 3H).

Example 848

5-(3-Fluoro-2′-pyrimidin-5-ylbiphenyl-4-yl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromopyrimidine in Step A. MS (ESI): mass calcd. forC₂₀H₁₄FN₅, 343.12; m/z found, 344.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ9.01 (s, 1H), 8.61 (s, 2H), 8.32-8.27 (m, 1H), 8.17 (d, J=1.4, 1H),7.88-7.78 (m, 1H), 7.63-7.50 (m, 4H), 7.11-7.00 (m, 2H).

Example 849

5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 838 using 5-bromopyrimidine-2-carbonitrile in Step A. MS (ESI):mass calcd. for C₂₁H₁₃FN₆, 368.12; m/z found, 369.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.73 (s, 2H), 8.37-8.33 (m, 1H), 8.04 (d, J=1.5, 1H), 7.80(m, J=8.1, 1H), 7.68-7.55 (m, 4H), 7.11 (dd, J=12.1, 1.7, 1H), 7.01 (dd,J=8.1, 1.7, 1H).

Example 850

5-[3-Fluoro-2′-(2-morpholin-4-ylpyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using 4-(5-bromopyrimidin-2-yl)morpholine in Step A. MS(ESI): mass calcd. for C₂₄H₂₁FN₆O, 428.18; m/z found, 429.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.36-8.32 (m, 1H), 8.14 (s, 2H), 8.04 (d, J=1.5,1H), 7.83-7.77 (m, 1H), 7.54-7.38 (m, 4H), 7.09-7.07 (m, 1H), 7.06 (dd,J=7.1, 1.6, 1H), 3.76-3.66 (m, 8H).

Example 851

1-{4-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1H-pyrazol-1-yl}-2-methylpropan-2-ol

The title compound was prepared in a manner similar to that described inExample 838 using 1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-ol inStep A. MS (ESI): mass calcd. for C₂₃H₂₂FN₅O, 403.18; m/z found, 404.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.37-8.32 (m, 1H), 8.07 (d, J=1.5,1H), 7.85-7.78 (m, 1H), 7.53-7.48 (m, 1H), 7.44-7.37 (m, 1H), 7.35 (dd,J=5.0, 1.1, 2H), 7.32 (d, J=0.9, 1H), 7.25 (d, J=0.8, 1H), 7.15 (dd,J=8.0, 1.7, 1H), 7.04 (dd, J=12.3, 1.7, 1H), 3.98 (s, 2H), 1.07 (s, 6H).

Example 852

5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylateand 2-bromo-1-chloro-4-(trifluoromethyl)benzene in Step A, followed byremoval of the Boc group. To a stirred solution of tert-butyl4-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)-[,1′-biphenyl]-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (68 mg, 0.13mmol) in DCM (2 mL) was added TFA (0.56 mL, 7.3 mmol) at roomtemperature. When analysis by LCMS indicated the reaction was complete,the stir-bar was removed, the reaction mixture concentrated to dryness,and the residue subjected to HPLC purification to provide the titlecompound. MS (ESI): mass calcd. for C₂₂H₁₈F₄N₄, 414.15; m/z found, 415.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.41-8.37 (m, 1H), 8.13 (d, J=1.5,1H), 8.03-7.96 (m, 1H), 7.78-7.72 (m, 1H), 7.64 (d, J=1.8, 1H), 7.61 (d,J=8.0, 1H), 7.37 (dd, J=8.0, 1.7, 1H), 7.33 (dd, J=12.1, 1.7, 1H), 5.89(m, 1H), 3.85-3.75 (m, 2H), 3.19 (t, J=6.0, 2H), 2.33-2.22 (m, 2H).

Example 853

5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 838 using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine and2-bromo-1-chloro-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₁₄F₄N₆, 426.12; m/z found, 427.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.34 (s, 1H), 8.16 (d, J=1.2, 2H), 8.10 (s, 1H), 7.92-7.86 (m,1H), 7.80 (d, J=8.3, 1H), 7.78 (d, J=1.7, 1H), 7.69 (d, J=8.0, 1H),7.23-7.08 (m, 2H).

Example 854

5-{2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]phenyl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 427 using(6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and5-(2-chlorophenyl)pyrimidin-2-amine. MS (ESI): mass calcd. forC₁₉H₁₄FN₇, 359.13; m/z found, 360.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.93 (s, 2H), 8.31-8.28 (m, 1H), 8.19 (s, 2H), 7.64 (dd, J=12.0, 1.9,1H), 7.59-7.51 (m, 4H).

Example 855

5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 427 using5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amineand 5-(2-bromophenyl)pyrimidin-2-amine. MS (ESI): mass calcd. forC₁₉H₁₅N₇, 341.14; m/z found, 342.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.97 (s, 2H), 8.47 (dd, J=2.3, 0.9, 1H), 8.16 (s, 2H), 7.86 (dd, J=8.2,0.9, 1H), 7.80 (dd, J=8.2, 2.3, 1H), 7.59-7.49 (m, 4H).

Example 856

5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

Title compound was prepared using conditions analogous to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amineand 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd.for C₁₉H₁₇FN₄O₂S, 384.11; m/z found, 385.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.62-8.58 (m, 1H), 8.12 (d, J=1.5, 1H), 7.99 (m, 1H), 7.76-7.71(m, 1H), 7.49-7.45 (m, 1H), 7.46-7.38 (m, 4H), 4.69 (s, 2H), 3.30-3.04(m, 4H), 2.39-2.11 (m, 2H).

Example 857

5-[2′-(1,1-Dioxido-1,2-thiazinan-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine

Title compound was prepared using conditions analogous to thosedescribed in Example 1 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 2-(2-bromophenyl)-1,2-thiazinane 1,1-dioxide. MS (ESI): mass calcd.for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.48-8.43 (m, 1H), 8.38-8.33 (m, 1H), 8.08-8.02 (m, 1H), 7.62(m, 1H), 7.45-7.39 (m, 4H), 7.34 (dd, J=12.5, 1.7, 1H), 3.76-3.65 (m,2H), 3.24-3.10 (m, 2H), 3.00-2.89 (m, 2H), 2.35-2.23 (m, 2H), 2.22-2.10(m, 2H).

Example 858

5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine

Title compound was prepared using methods analogous to those describedin Example 384 using5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amineand 2-(2-bromophenyl)isothiazolidine 1,1-dioxide. MS (ESI): mass calcd.for C₁₉H₁₇FN₄O₂S, 384.11; m/z found, 385.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.58 (d, J=1.4, 2H), 7.78-7.71 (m, 1H), 7.69-7.58 (m, 1H),7.50-7.32 (m, 4H), 7.29-7.20 (m, 1H), 5.21 (s, 2H), 3.77 (t, J=6.8, 1H),3.43-3.17 (m, 2H), 2.67-2.47 (m, 1H), 2.42-2.17 (m, 2H).

Example 859

5-[2-Fluoro-4-(2-pyrrolidin-1-ylpyridin-3-yl)phenyl]pyrazin-2-amine

Title compound was prepared using methods analogous to those describedin Example 377 using (2-(pyrrolidin-1-yl)pyridine-3-yl)boronic acid and5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): masscalcd. for C₁₉H₁₈FN₅, 335.15; m/z found, 336.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.61-8.56 (m, 1H), 8.22-8.17 (m, 1H), 8.12 (s, 1H), 7.97-7.88(m, 1H), 7.45-7.38 (m, 1H), 7.29-7.23 (m, 1H), 7.21-7.14 (m, 1H),6.75-6.67 (m, 1H), 4.67 (s, 2H), 3.28-3.10 (m, 4H), 1.87-1.73 (m, 4H).

Example 860

1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidin-2-one

Title compound was prepared using analogous conditions to thosedescribed in Example 1 utilizing5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amineand 1-(2-bromophenyl)pyrrolidin-2-one. MS (ESI): mass calcd. forC₂₀H₁₇FN₄O, 348.14; m/z found, 349.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.54-7.14 (m, 6H), 6.72 (s,2H), 3.44 (t, J=6.7, 2H), 2.26 (t, J=7.9, 2H), 1.97-1.87 (m, 2H).

The following Examples 1-13 summarized in Table 4 are prophetic andunless otherwise specified, can be readily synthesized by a personskilled in the art utilizing the above described reaction schemes or bysynthesis routes generally known to a person skilled in the art. Oneskilled in the art based on presently disclosed compounds would concludethe following prophetic compounds to be active against FLAP.

TABLE 4 Prophetic Examples STRUCTURE No. NAME

1 4′-(6-Aminopyridazin-3-yl)-3′- fluorobiphenyl-2-sulfonamide

2 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-(trifluoromethyl)biphenyl-2- sulfonamide

4 N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide

5 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-methoxybiphenyl-2-sulfonamide

6 (3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3- carboxamide

7 (3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3- carboxamide

8 5-[3-Fluoro-2′-(morpholin-4- ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine

9 5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine

10 1-{[4′-(2-Aminopyrimidin-5-yl)-3′- fluorobiphenyl-2-yl]sulfonyl}-4-(pentafluoroethyl)piperidin-4-ol

11 tert-Butyl (1-{[3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2- yl]sulfonyl}piperidin-4-yl)carbamate

12 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-sulfonamide

13 4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2- sulfonamideD) General Administration, Formulation, and Dosages

The present invention provides substituted heteroaryl ketone compoundswhich are useful as FLAP modulators.

The invention features a method for treating a subject in need thereofwith an FLAP-mediated disease and/or disorder, said method comprisingadministering to the subject a therapeutically effective amount of acompound of the invention. In particular, the invention also provides amethod for treating or inhibiting the progression of an FLAP-mediateddisease and/or disorder, or associated symptoms or complications thereofin a subject afflicted with such a disease and/or disorder, wherein themethod comprises administering to the subject a therapeuticallyeffective amount of a compound of the invention.

Embodiments of the present invention include a method wherein thecompound of Formula (I) is a FLAP modulator.

Embodiments of the present invention include a use of the compound ofFormula (I) in the manufacture of a medicament for treating anFLAP-mediated disease and/or disorder.

Embodiments of the present invention include a use of the compound ofFormula (I) as a medicine.

The compounds of Formula (I) have an FLAP-modulating effect and areuseful as therapeutic agents for various FLAP-mediated disorders and/ordisorders, or associated symptoms or complications, for example,respiratory disorders, cardiac and cardiovascular diseases, autoimmunedisorders, carcinogenesis, and associated symptoms or complicationsthereof.

The compounds of Formula (I) may be administered orally or parenterally,and after formulation into preparations suitable for the intendedadministration route, they can be used as therapeutic agents fortreating an FLAP-mediated disease and/or disorder. FLAP-mediateddiseases and/or disorders include, but are not limited, diseases and/ordisorders that are related to leukotriene synthesis pathway, andtherefore may be treated, controlled or in some cases prevented, bytreatment with the compounds of this invention.

One aspect of the present invention provides a method for the treatmentof diseases and/or disorders, or associated symptoms or complicationsthereof, responsive to the modulation of FLAP in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound of Formula (I) or aform thereof.

Another aspect of the present invention provides a method for thetreatment of a disease and/or disorder selected from the groupconsisting of respiratory diseases and/or disorders, cardiac andcardiovascular diseases and/or disorders, autoimmune diseases and/ordisorders, carcinogenesis, and associated symptoms or complicationsthereof, in a subject in need thereof which comprises administering tothe subject a therapeutically or prophylactically effective amount of acompound of Formula (I) or a form thereof.

More specifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, fibrotic lung diseases, acuterespiratory distress syndrome and chronic obstructive pulmonary disease,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of Formula (I) or a form thereof.

Furthermore, this invention is directed to a method of treatingmyocardial infarction, atherosclerosis and stroke aortic aneurisms,atherosclerosis, or associated symptoms or complications thereof, in asubject afflicted with such a disease and/or disorder, wherein themethod comprises administering to the subject a therapeutically orprophylactically effective amount of a compound of Formula (I) or a formthereof.

Yet, this invention is also directed to a method of treating rheumatoidarthritis, inflammatory bowel disease, nephritis, spondyloarthritis,polymyositis, dermatomyositis, gouty effusions, systemic lupuserythematosus, systemic sclerosis, Alzheimer's disease, multiplesclerosis, allergic rhinitis, allergic dermatitis and asthma, whereinthe method comprises administering to the subject a therapeutically orprophylactically effective amount of a compound of Formula (I) or a formthereof.

Finally, this invention is also directed to a method of treating tumorcell proliferation, differentiation, and apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells,wherein the method comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofFormula (I) or a form thereof.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising at least one compound of Formula (I) or a formthereof, and a pharmaceutically acceptable carrier.

The invention also features a method for treating a subject in needthereof with an FLAP-mediated disease and/or disorder, said methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising at least one compoundof the invention.

Yet another aspect of the present invention relates to the use of acompound of Formula (I) or a form thereof, for the manufacture of amedicament useful for the treatment of an FLAP-mediated disease and/ordisorder in a subject in need thereof.

In a clinical use of the compounds of the invention,pharmaceutically-acceptable additives may be added thereto to formulatevarious preparations in accordance with the intended administrationroute thereof, and the preparations may be administered.

Various additives generally used in the field of pharmaceuticalcompositions may be used herein, including, for example, gelatin,lactose, sucrose, titanium oxide, starch, crystalline cellulose, methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, cornstarch, microcrystalline wax, white petrolatum, magnesium metasilicatealuminate, anhydrous calcium phosphate, citric acid, trisodium citrate,hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinylpyrrolidone, magnesium stearate, palmitoleic acid, lightsilicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic,propylene glycol, polyalkylene glycol, cyclodextrin, andhydroxypropylcyclodextrin.

Combined with such additives, the compound of the invention may beformulated into various forms of preparations, for example, solidpreparations such as tablets, capsules, granules, powders andsuppositories; and liquid preparations such as syrups, elixirs andinjections. These preparations can be produced in any method known inthe field of pharmaceutical compositions. The liquid preparations may bein such a form that is dissolved or suspended in water or in any othersuitable medium before use. Especially for injections, the preparationmay be dissolved or suspended, if desired, in a physiological saline orglucose solution, and a buffer and a preservative may be added thereto.

The compounds of the invention are effective for animals, includinghumans and other mammals. Any ordinary physician, veterinarian orclinician may readily determine the necessity, if any, of treatment withan instant compound.

Those of skill in the treatment of diseases and/or disorders, orassociated symptoms or complications thereof, mediated by FLAP candetermine the effective daily amount from the test results presentedhereinafter and other information. The exact dosage and frequency ofadministration depends on the particular compound of invention used, theparticular disease and/or disorder, or associated symptoms orcomplications thereof, being treated, the severity of the disease and/ordisorder, or associated symptoms or complications thereof, beingtreated, the age, weight and general physical condition of theparticular patient as well as other medication the patient may betaking, as is well known to those skilled in the art. Furthermore, it isevident that said effective daily amount may be lowered or increaseddepending on the response of the treated patient and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention. The effective daily amount ranges mentioned herein aretherefore only guidelines in practicing the present invention.

Preferably, the method for the treatment of the FLAP diseases and/ordisorders described in the present invention using any of the compoundsas defined herein, the dosage form will contain a pharmaceuticallyacceptable carrier containing between from about 1 mg to about 1000 mg;particularly from about 0.5 mg to about 500 mg of the compound, and maybe constituted into any form suitable for the mode of administrationselected. The dosages, however, may be varied depending upon therequirement of the subjects, the severity of the disease and/ordisorder, or associated symptoms or complications thereof, being treatedand the compound being employed. The use of either daily administrationor post-periodic dosing may be employed.

When the compound of the invention is, for example, put into clinicaluse, then its dose and its administration frequency may vary dependingon the sex, the age, the body weight and the condition of the patientand on the type and the range of the necessary treatment with thecompound. For oral administration, in general, the dose of the compoundmay be in a range of from about 0.01 mg/kg/day to about 100 mg/kg ofbody weight/day or in a range of from about 0.03 mg/kg/day to about 1mg/kg/day. The oral administration frequency is preferably from one to afew times per day. For parenteral administration, the dose may be in arange of from about 0.001 mg/kg/day to about 10 mg/kg/day, in a range offrom about 0.001 mg/kg/day to about 0.1 mg/kg/day or, in a range of fromabout 0.01 mg/kg/day to about 0.1 mg/kg/day. The parenteraladministration frequency is preferably from one to a few times per day.For oral administration, the compositions are preferably provided in theform of tablets containing from about 1.0 mg to about 1000 mg of theactive ingredient, particularly 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg,600 mg, 750 mg, 800 mg, 900 mg, and 1000 mg of the active ingredient forthe symptomatic adjustment of the dosage to the patient to be treated.The compounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

Ordinary physicians, veterinarians and clinicians may readily determinethe effective dose of the pharmaceutical compound necessary to treat,prevent, inhibit, retard or stop the intended disease, and may readilytreat the diseased patient with the compound.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day(particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, moreparticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and maybe given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day(particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, moreparticularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even moreparticularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, autoinjector devices orsuppositories for administration by oral, intranasal, sublingual,intraocular, transdermal, parenteral, rectal, vaginal, dry powderinhaler or other inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for 1 to 4 times perday, preferably once or twice per day administration; for example, aninsoluble salt of the active compound, such as the decanoate salt, maybe adapted to provide a depot preparation for intramuscular injection.

The preparation may contain the compound of the invention in an amountin a range of from about 1.0 to about 100% by weight or, in a range offrom about 1.0 to about 60% by weight of the preparation. Thepreparation may contain any other therapeutically-effective compound.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are intended tobe encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, cis-trans isomers, and enantiomers thereof areencompassed within the scope of the present invention.

E) Use

Dosages

For preparing pharmaceutical compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable gildants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active form of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimetllitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agents include pharmaceutical gradelecithins. Suitable flocculating agents include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms; however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 5000 mg;preferably, the dose will be in the range of from about 1 mg to about100 mg per day for an average human. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. The above dosagesare thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as FLAP modulators is required for a subject in needthereof.

In their use, the compounds of the invention may be combined with anyother therapeutic agents that are useful for the treatment of anFLAP-mediated disorder.

The combination includes not only the composition of compounds of theinvention and one other active substance but also the composition ofcompounds of the invention and two or more other active substances ornon-drug therapy. The scope of possible combinations of a compound ofthe invention and one, two or more active substances are within theknowledge of one skilled in the art for the treatment of anFLAP-mediated disorder.

Specifically, the combination of a FLAP modulator with prostaglandinmodulators, cyclooxygenase-1 modulators, or cyclooxygenase-2 modulatorsmight be used to treat inflammatory and autoimmune diseases and/ordisorders as well as cardiovascular diseases and/or disorders, orvascular injury (Z. Yu et al., “Disruption of the 5-lipoxygenase pathwayattenuates atherogenesis consequent to COX-2 deletion in mice,” Proc.Natl. Acad. Sci. USA, 2012, 109(17), 6727-32; Z. Yu et al., “MyeloidCell 5-Lipoxygenase Activating Protein Modulates the Response toVascular Injury,” Circ. Res., 2012, Epub December 18). Due to thesynergy of histamine and leukotrienes, the combination of a FLAPmodulator and a histamine receptor 1 or 4 antagonist might have utilityin treating respiratory, allergic, dermatological and autoimmunedisorders (A. Reicin et al., “Montelukast, a leukotriene receptorantagonist, in combination with loratadine, a histamine receptorantagonist, in the treatment of chronic asthma,” Arch. Intern. Med.,2000, 160(16), 2418-88; S. Sanada et al., “The effectiveness ofmontelukast for the treatment of anti-histamine-resistant chronicurticaria,” Arch. Dermatol. Res., 2005, 297(3), 134-38).

Formulations

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

F) Biological Examples

The ability of the compounds of the present invention to treat aFLAP-mediated disease and/or disorder, or associated symptoms orcomplications thereof, was determined using the following procedures.Binding assay data represent the average value obtained from twodifferent assay plates, with samples run in duplicate on each plate.Human whole blood assay data represent a single replicate on an assayplate using whole blood from at least one healthy donor. Certain FLAPbinding and human whole blood assay data are presented in Table 5.

FLAP Binding Assay

The assay below is used to test the modulatory activity of compoundsagainst FLAP. Human and mouse FLAP-encoding DNA was amplified bypolymerase chain reaction and cloned into pFastBacl (Invitrogen) with aNH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9)cells. FLAP-containing membranes were prepared as was a FITC-labeledFLAP modulator[5-[({[2-(2-{3-[3-(tert-Butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid]. The FLAP binding assay is performed in HTRF format (homogeneoustime resolved fluorescence). FLAP-containing membranes (1 μg/well finalfor human) are incubated in the presence of the HTRF ligand,[5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid](25 nM final), a terbium labeled anti-His tag antibody (0.5 ng/wellfinal, from Cisbio) and compounds. The reaction is allowed to proceedfor two hours after which the plate is read on an Envision plate readerin HTRF mode. Data are expressed as a HTRF ratio.

For human FLAP binding assays, data are analyzed with 3DX Explorersoftware. A ratio is calculated with the relative light units at 520 nmover the relative light units at 495 nm. For analysis, data are importedinto 3DX and aggregated as the average of duplicates of the calculatedratios in order to calculate K_(i) and ICo₅₀ values.

Human Whole Blood Assay

An in vitro cellular assay was performed using human whole bloodcollected in heparin-containing tubes, which was used to test theability of compounds to modulate the leukotriene pathway in human wholeblood. The blood was diluted 1:1 in RPMI medium, pre-incubated for 15min at 37° Celsius with test compounds at various concentrations, andthen stimulated with calcium ionophore, A23187 (7 μg/mL), for 30 min at37° Celsius. The samples were then centrifuged and plasma was removed.The plasma was diluted in assay buffer and LTB₄ levels were measuredusing a commercial kit (Enzo Life Sciences). The concentration of eachcompound that was required for half-maximal inhibition (modulation) ofrecombinant enzyme activity (IC₅₀) was calculated by a 4-parameterequation using the program GraphPad Prism (GraphPad software).

TABLE 5 FLAP binding and Human Whole Blood assay data FLAP Binding wildtype HTRF Cmp No. K_(i) (μM) LTB4 IC₅₀ 1:1 (μM) 1 0.217 0.860 2 0.2860.358 3 >10 4 0.001 0.018 5 0.035 0.370 6 0.001 0.033 7 0.002 0.014 80.001 0.012 9 0.003 0.060 10 0.003 0.053 11 0.002 0.015 12 0.002 0.02113 0.001 0.018 14 0.003 0.032 15 0.010 0.059 16 0.006 0.018 17 0.0020.025 18 0.002 0.070 19 0.002 0.050 20 0.001 0.009 21 0.002 0.035 220.002 0.048 23 0.001 0.013 24 0.002 0.048 25 0.003 0.023 26 0.001 0.02627 0.029 10.000 28 0.090 0.325 29 0.059 0.030 30 0.095 31 0.004 0.036 320.008 0.030 33 0.304 34 0.031 0.334 35 0.036 0.094 36 0.010 0.120 370.030 0.676 38 0.033 0.177 39 0.008 0.075 40 0.014 0.112 41 0.014 2.68742 0.011 0.149 43 0.002 0.111 44 0.007 0.058 45 0.003 0.010 46 0.0570.194 47 0.001 0.017 48 0.011 0.158 49 0.002 0.021 50 0.001 0.015 510.004 0.042 52 0.004 0.155 53 0.003 0.238 54 0.020 0.023 55 0.001 1.23256 0.011 3.516 57 0.015 0.252 58 0.005 0.991 59 0.020 1.017 60 0.0280.464 61 0.011 0.117 62 0.142 0.111 63 0.006 0.028 64 0.002 0.006 650.049 0.322 66 0.021 0.069 67 0.003 0.012 68 0.001 0.006 69 0.001 0.00870 0.002 0.010 71 0.002 0.023 72 0.111 0.168 73 0.062 0.077 74 0.0060.061 75 0.012 0.185 76 0.002 0.027 77 0.003 0.342 78 0.001 0.166 790.005 0.150 80 0.004 0.088 81 0.006 0.152 82 0.001 0.018 83 0.001 0.01984 0.003 0.097 85 0.002 0.020 86 0.003 0.027 87 0.003 0.075 88 0.0070.036 89 0.006 0.043 90 0.001 0.012 91 0.005 0.028 92 0.325 0.222 930.127 0.128 94 0.076 0.235 95 0.010 0.053 96 0.354 >10 97 0.008 0.042 980.008 0.039 99 0.002 0.030 100 0.001 0.024 101 0.002 0.014 102 0.0000.035 103 0.000 0.017 104 0.012 >1 105 0.025 0.481 106 0.019 >1 1070.016 0.132 108 0.010 0.049 109 0.001 0.018 110 0.003 0.029 111 0.0040.058 112 0.007 0.154 113 0.010 0.145 114 0.012 0.221 115 0.004 0.108116 0.001 0.012 117 0.001 0.007 118 0.000 0.006 119 0.003 0.022 1200.001 0.017 121 0.000 0.010 122 0.001 0.018 123 0.083 1.125 124 0.0350.217 125 0.050 >10 126 0.141 0.572 127 0.002 0.035 128 0.001 0.038 1290.004 0.534 130 0.129 0.633 131 0.144 0.695 132 0.002 0.011 133 0.0010.032 134 0.001 >1 135 0.000 0.016 136 0.001 0.015 137 0.003 0.044 1380.011 0.174 139 0.133 0.341 140 0.001 0.011 141 0.001 0.003 142 0.0150.041 143 0.008 0.049 144 0.015 0.097 145 0.017 0.021 146 0.019 0.168147 0.001 0.102 148 0.002 0.008 149 0.005 0.082 150 0.001 0.011 1510.001 0.114 152 0.081 0.537 153 0.003 0.007 154 0.029 1.044 155 0.0120.103 156 0.351 >10 157 0.010 1.841 158 0.001 0.001 159 0.001 0.001 1600.000 0.005 161 0.000 0.048 162 0.005 0.122 163 0.001 0.595 164 0.0010.333 165 0.018 0.879 166 0.164 4.463 167 0.047 0.442 168 0.014 0.135169 0.003 0.023 170 0.001 0.012 171 0.002 0.013 172 0.004 0.020 1730.001 0.017 174 0.002 0.023 175 0.001 0.017 176 0.000 0.010 177 0.0000.302 178 1.323 179 0.000 0.002 180 0.002 0.037 181 0.007 0.240 1820.020 0.217 183 0.034 0.130 184 0.009 0.021 185 0.010 0.051 186 0.0190.021 187 0.066 0.069 188 0.201 1.185 189 0.173 1.649 190 0.058 0.471191 0.658 192 0.058 0.171 193 0.026 0.144 194 0.733 195 0.003 0.093 1960.010 0.104 197 0.010 0.083 198 0.083 0.375 199 0.039 0.250 200 0.0350.176 201 0.021 0.358 202 0.072 0.172 203 0.005 0.052 204 0.004 0.128205 0.008 0.066 206 0.002 0.043 207 0.017 0.205 208 0.000 0.014 2090.001 0.034 210 0.000 0.020 211 0.001 0.006 212 0.001 0.005 213 0.0020.025 214 0.012 0.138 215 0.002 0.012 216 0.002 0.016 217 0.001 0.009218 0.003 0.029 219 0.005 0.031 220 0.205 0.219 221 0.300 0.854 2220.118 0.638 223 0.663 224 0.293 0.516 225 0.856 226 0.211 0.329 2270.670 228 1.055 229 1.067 230 1.205 5.000 231 0.135 0.564 232 0.358 2330.637 234 0.025 0.238 235 0.036 0.285 236 0.057 0.443 237 0.008 0.134238 0.005 0.038 239 0.006 240 0.002 0.021 241 0.015 0.061 242 0.0010.004 243 0.003 0.120 244 0.029 0.211 245 0.045 0.233 246 0.199 0.302247 0.089 0.197 248 0.050 0.124 249 0.059 0.094 250 0.038 0.077 2510.005 0.068 252 0.127 0.206 253 0.134 0.191 254 0.080 0.586 255 0.0080.076 256 0.035 0.073 257 0.154 1.125 258 0.243 0.202 259 0.005 0.034260 0.010 0.057 261 0.006 0.075 262 0.018 0.046 263 0.169 0.207 2640.028 0.144 265 0.045 0.160 266 0.184 0.464 267 0.154 0.350 268 0.0110.056 269 0.015 0.087 270 0.057 1.065 271 0.051 0.606 272 0.032 0.125273 0.009 0.105 274 275 0.065 0.192 276 0.023 0.325 277 0.052 >1 2780.036 0.095 279 0.070 0.149 280 0.003 0.087 281 0.061 0.044 282 0.7500.280 283 0.009 0.119 284 0.042 1.037 285 0.003 0.111 286 0.142 0.206287 0.009 0.074 288 0.103 0.420 289 0.022 0.036 290 0.940 291 0.0070.421 292 0.012 1.029 293 >10 294 0.002 0.248 295 0.025 0.110 296 0.0050.066 297 0.005 0.045 298 0.081 1.166 299 0.121 300 0.013 0.120 3010.013 0.204 302 2.500 303 0.612 304 >10 305 0.002 0.078 306 0.397 3070.004 0.416 308 >10 309 0.214 1.785 310 0.492 311 0.747 312 0.262 0.376313 0.397 0.574 314 0.089 0.178 315 0.001 0.027 316 0.746 317 0.335 >10318 0.689 2.001 319 0.204 3.263 320 0.129 1.084 321 0.505 8.486 3220.032 0.138 323 0.770 6.644 324 0.019 0.101 325 0.004 0.091 326 0.0030.029 327 0.002 0.039 328 0.015 0.119 329 0.012 0.066 330 0.012 0.088331 0.014 0.062 332 0.065 0.125 333 0.045 0.671 334 0.012 0.067 3350.002 0.037 336 0.004 0.065 337 2.500 338 0.199 1.094 339 2.500 3400.104 0.321 341 >10 342 0.002 0.117 343 0.004 0.057 344 0.081 >10 3450.028 0.259 346 0.005 0.095 347 0.077 0.161 348 0.005 0.106 349 0.0010.013 350 0.002 0.026 351 0.017 0.297 352 0.016 0.064 353 0.001 0.020354 0.037 0.093 355 0.005 0.029 356 0.032 0.107 357 0.114 1.128 3580.055 >10 359 0.004 0.054 360 0.022 0.067 361 0.005 0.026 362 0.0010.047 363 0.001 0.184 364 0.003 0.150 365 0.003 0.060 366 0.001 0.040367 0.001 0.006 368 0.013 0.178 369 0.017 0.375 370 0.002 0.088 3710.001 0.015 372 0.025 0.031 373 0.001 0.007 374 0.001 0.011 375 0.0020.031 376 0.000 0.010 377 0.033 0.979 378 0.001 0.016 379 0.001 0.033380 0.001 0.046 381 0.005 0.141 382 0.000 0.011 383 0.008 1.633 3840.004 0.082 385 0.042 1.083 386 0.002 0.077 387 0.008 0.253 388 0.0020.037 389 0.013 0.137 390 0.000 0.010 391 0.002 0.056 392 0.001 0.016393 0.001 0.012 394 >10 395 0.009 0.032 396 0.008 0.137 397 >10 3980.034 1.132 399 0.028 0.358 400 0.014 0.729 401 0.158 0.538 402 0.0920.522 403 0.070 0.389 404 0.155 1.490 405 0.100 2.708 406 0.135 4.314407 >10 408 0.128 1.142 409 >10 410 0.004 0.088 411 0.036 1.968 4120.019 0.509 413 0.019 0.448 414 0.065 0.120 415 0.011 0.037 416 1.249417 0.108 0.726 418 1.250 419 1.369 420 0.086 3.280 421 0.028 >10 4220.003 0.146 423 0.284 4.795 424 0.010 >10 425 0.002 0.111 426 0.0020.073 427 0.054 1.599 428 0.004 0.004 429 0.013 0.209 430 0.005 0.059431 0.001 0.009 432 0.004 0.019 433 0.001 0.025 434 0.001 0.036 4350.009 0.166 436 0.308 3.277 437 0.023 0.381 438 0.001 0.017 439 0.0630.300 440 0.031 0.215 441 0.001 0.006 442 0.001 0.009 443 0.343 3.331444 0.183 >10 445 0.001 0.008 446 0.304 1.371 447 0.003 0.144 448 0.0100.112 449 0.022 0.079 450 0.074 0.340 451 0.002 0.038 452 0.081 1.954453 >10 >10 454 0.012 0.345 455 0.001 0.094 456 0.003 0.114 457 0.0030.140 458 0.004 0.053 459 >10 460 >10 461 0.041 0.209 462 0.002 0.062463 0.982 464 0.121 >10 465 0.186 0.957 466 0.254 0.990 467 0.250 2.827468 0.620 469 0.250 2.347 470 0.620 471 0.250 3.395 472 0.145 2.524 4730.113 1.411 474 0.021 2.653 475 0.750 476 0.032 0.891 477 0.016 0.738478 0.250 479 0.006 0.571 480 0.354 481 1.912 482 0.120 483 0.354 4840.078 3.465 485 >10 486 2.500 487 0.054 0.444 488 0.097 1.653 489 0.0200.307 490 0.354 0.269 491 0.015 0.215 492 0.015 0.155 493 0.007 0.303494 0.032 0.099 495 0.004 0.509 496 0.019 0.165 497 0.025 0.510 4980.016 0.111 499 0.433 500 0.048 0.139 501 0.359 502 0.083 0.363 5030.014 0.092 504 0.768 505 0.018 0.071 506 >10 507 >10 508 0.790 5090.147 0.093 510 1.939 511 0.213 0.323 512 0.443 0.470 513 >10 514 0.1320.148 515 >10 516 >10 517 >10 518 >10 519 >10 520 >10 521 0.005 0.013522 0.348 0.393 523 0.001 0.025 524 0.001 0.018 525 0.003 0.036 5260.008 0.019 527 0.074 0.183 528 0.005 0.034 529 0.036 0.090 530 0.0341.112 531 0.008 0.323 532 0.006 0.032 533 0.005 0.023 534 0.012 0.069535 0.001 0.017 536 0.021 0.068 537 0.003 0.042 538 0.020 0.330 5390.002 0.052 540 0.016 0.085 541 0.012 0.066 542 0.107 0.311 543 0.4444.165 544 0.028 1.652 545 0.012 0.050 546 0.148 0.253 547 0.035 0.104548 0.467 0.741 549 0.009 0.123 550 0.002 0.016 551 0.000 0.021 5520.005 0.102 553 0.019 0.430 554 0.002 0.039 555 0.002 0.024 556 0.0010.013 557 0.147 1.066 558 0.012 0.210 559 0.002 0.055 560 0.005 0.095561 0.004 0.043 562 0.055 0.226 563 0.020 0.328 564 0.200 0.583 5650.081 0.984 566 >10 567 1.135 568 2.500 569 0.070 0.335 570 0.035 1.183571 0.002 0.091 572 0.370 573 0.114 574 0.015 0.494 575 0.750 576 0.0080.116 577 0.010 0.091 578 0.025 0.956 579 0.095 1.544 580 0.055 5.000581 0.060 2.823 582 >10 583 >10 584 >10 585 >10 586 >10 587 >10 5880.133 >10 589 >10 590 >10 591 ~2.49 592 >10 593 >10 594 >10 595 ~2.49596 >10 597 ~2.49 598 >10 599 >10 600 >10 601 >10 602 0.0006 0.0167 6030.0276 >10 604 0.0050 0.0894 605 0.0019 0.0978 606 0.0463 2.624 6070.1384 0.1520 608 0.0287 0.0539 609 0.2464 0.7677 610 0.0274 0.1170 6110.2489 0.5626 612 0.0146 0.0420 613 0.2146 0.5565 614 615 616 617 6180.0146 0.2109 619 0.0034 0.0451 620 0.0019 0.0132 621 0.0050 0.1006 6220.0461 0.3401 623 0.0049 0.0935 624 625 0.0078 0.1727 626 0.0062 0.0453627 0.0437 0.3661 628 0.3362 629 0.8358 630 1.8950 631 >10 632 1.2677633 >10 634 0.3108 1.470 635 1.0869 636 0.0046 0.1072 637 0.0188 0.3975638 0.0014 0.0148 639 0.0072 0.0670 640 1.3397 641 >10 642 0.0788 0.9806643 0.3225 4.2874 644 >10 645 646 647 648 649 >10 650 0.8316 651 0.30621.5363 652 0.0627 0.8425 653 0.0173 0.5267 654 0.1303 1.0459 655 0.50341.8302 656 1.3957 657 0.0735 2.3415 658 0.5717 659 ~0.7500 6600.0833 >10 661 ~2.49 662 ~1.22 663 0.0058 0.0347 664 0.0050 >1 6650.0026 0.0224 666 0.0032 0.0361 667 0.0060 0.0396 668 0.0230 0.1897 6690.0040 0.1064 670 0.0977 0.5255 671 0.0157 0.1645 672 0.0137 0.1964 6730.1343 0.1013 674 0.0024 0.0174 675 0.0007 0.0551 676 0.2339 3.7145677 >10 678 >10 679 0.1316 0.2054 680 0.6097 1.0502 681 0.0522 0.1057682 0.2239 0.2638 683 0.6021 0.2800 684 0.0463 0.1342 685 0.0523 0.1148686 0.3343 1.4900 687 0.7399 3.5456 688 0.6955 1.1844 689 0.4846 0.7872690 0.1771 0.1175 691 >10 692 0.0533 0.1097 693 0.0495 0.1032 694 0.67621.0115 695 0.0084 0.3355 696 ~0.2499 3.27492 697 >10 698 0.0087 0.1117699 700 >10 701 ~1.41 702 ~0.3041 703 >10 704 0.1025 0.1906 705 0.08690.2891 706 0.0796 0.3620 707 0.0327 0.1266 708 0.0235 0.1416 709 0.00540.2682 710 0.0137 0.05651 711 0.0417 0.1420 712 0.0019 0.05233 7130.0017 0.05339 714 0.0024 0.03311 715 0.0082 0.1858 716 >10 717 1.0083718 >10 719 >10 720 >10 721 >10 722 >10 723 >10 724 >10 725 1.2960 7260.9041 727 0.4838 1.1740 728 0.7813 729 0.0647 0.8609 730 0.0067 0.1359731 0.0147 0.05132 732 0.5571 733 >10 734 >10 735 0.0320 0.2722 7360.3303 0.4144 737 0.9842 738 0.2400 2.9546 739 0.3701 1.1132 740 >10 7410.0046 0.02633 742 0.0029 0.02572 743 0.0016 0.02165 744 0.0155 0.13173745 0.0117 0.11073 746 0.0020 0.13699 747 0.0271 0.26224 748 >10 7490.2455 0.46752 750 1.1582 751 0.0809 1.05657 752 0.1352 0.29915 7530.0044 0.02130 754 0.0699 0.37722 755 0.9395 756 >10 757 0.0052 0.016206758 0.5569 759 >10 760 1.1559 761 >10 762 0.1589 0.44177 763 1.1148764 >10 765 >10 766 1.9090 767 >10 768 0.5728 769 1.5449 770 >10 771 >10772 >10 773 0.2227 0.63899 774 775 776 777 778 >10 779 ~2.49 780 >10 7810.7295 782 >10 783 >10 784 0.0079 0.1105 785 0.0085 0.0575 786 0.06070.10485 787 0.0091 0.0979 788 0.0178 0.2715 789 0.1303 0.9392 790 0.00150.02533 791 >10 792 >10 793 0.2795 0.6419 794 0.0328 3.9355 795 0.00850.0686 796 0.3912 797 >10 798 0.2573 0.220039 799 >10 800 >10 801 >10802 >10 0.000993574 803 0.1065 0.241268 804 0.6359 805 0.0297 0.352777806 0.0018 0.048395 807 0.0058 0.0721606 808 0.0004 0.00637236 8090.0038 0.0376964 810 0.0006 0.00563897 811 0.3149 0.541252 812 0.00850.0120393 813 0.0339 0.0750585 814 0.0028 0.0209218 815 0.2555 0.128115816 0.0218 0.0460044 817 0.4629 818 0.0272 0.051606 819 0.0405 0.0474898820 0.0033 0.041639 821 >10 822 0.2804 0.099106 823 0.1923 0.0950605 8240.0103 0.0180053 825 0.2732 0.122321 826 0.0007 0.0199205 827 >10 8280.1153 0.259777 829 0.0032 0.00596486 830 0.0029 0.00555393 831 0.13090.0791589 832 1.3119 833 ~0.500034 834 0.0489 1.09069 835 ~0.353590.417157 836 0.0255 0.595114 837 ~1.74985 838 0.0286 0.350106 839 0.82972.78805 840 0.0127 0.0995864 841 0.1458 0.369658 842 0.0053 0.061038 8430.0156 0.0442792 844 0.5093 0.907193 845 >10 846 0.0105 0.0418215 8470.0081 0.0991289 848 0.0968 0.321736 849 0.0356 >1 850 0.0377 0.195434851 0.0326 0.359335 852 0.1179 1.34555 853 0.0047 0.0456037 854 1.2773855 >10 856 0.0605 0.083888 857 0.0280 0.205494 858 0.2097 0.369743 859~1.249 860 ~1.479

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

The invention claimed is:
 1. A compound of Formula (I)

wherein L is a bond, —CH₂—, —SO₂—, —CH₂—SO₂—, —SO₂—CH₂—, —SO₂—NR—,—SO₂—NR—CH₂—, —CH₂—SO₂—NR—, —NR—, —NR—SO₂—, —S—, —S—CH₂—, —CH₂—S—,—C(═O)—, —O—, —O—CH₂, —NR—C(═O)—, or —C(═O)—NR—, wherein R is H, C₁₋₂alkyl, C₁₋₂ alkyl-OH or cyclopropyl; R₁ is H, halo, methyl, CF₃, —O—CF₃,or —O—CH₃; R₂ is H, cyano, halo, 2-(trimethylsilyl)ethoxy, phenyl,C₁₋₆alkyl, heteroaryl, heterocyclyl, C₃₋₉cycloalkyl, provided R₂ is notH if L is a bond, and wherein said phenyl, C₁₋₆alkyl, heteroaryl,heterocyclyl or C₃₋₉cycloalkyl is optionally and independentlysubstituted selected from the group consisting of: methyl, ethyl, oxo,fluoro, hydroxyl, cyano, amino, methoxy, tert-butoxy, acetyl,cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azetidin-1-yl,azetidin-3-yl, pyrrolidin-1-yl, 2,4-dihydro-3H-1,2,4-triazol-3-one-4-yl,1H-imidazol-4-yl, pyrazin-2-yl, pyrimidin-2-yl,1,3-oxazolidin-2-one-5-yl, N-benzamide, 4-methylpiperazin-1-yl,morpholin-4-yl, CF₃, —SO₂—CH₃, —C(═O)-cyclopropyl, —NHCH₃, —N(CH₃)₂,—NHAc, —NHCO₂t-Bu, —CH₂—NH₂, —C(═O)—NH₂, —C(═O)—N(ethyl)₂,—NH—C(═O)—NH₂, —NH—C(═O)—CH₃, —C(═O)—(C₁-C₄alkyl), —C(═O)—OH,—C(═O)—NH(C₁-C₄alkyl) —(CH₂)_(n)—OH, and —(CH₂)_(n)—CN, wherein n is 1or 2; V is CH, CR′, or N, wherein R′ is methyl or F; W is CR″ or N,wherein R″ is H, F, hydroxyl, amino, CH₃ or —O—CH₃; ring A is selectedfrom the group consisting of:

R₃ is H, F, methyl, or —O—CH₃; R₃′ is H or F; R₄ is H, methyl, cyano,amino, halo, —COOH, or —O—CH₃; R₅ is H, methyl, cyano, or —CF₃; R₆ is H,cyano, amino, halo, or —CF₃; and R₇ is halo, amino, —CONH₂, cyano,—O—CH₃, —CF₃, or —COO-ethyl; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein L is a bond, —O—, —SO₂—NH—,—NH—SO₂—, —SO₂—, —S—, —C(═O)—, fluoro or —C(═O)—NH—; R₁ is H, bromo orCF₃; R₂ is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl,cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl,tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl,thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl,provided R₂ is not H if L is a bond, and wherein R₂ is optionallysubstituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH₂—NH₂; V isCH or N; W is CR″ or N, wherein R″ is H or F; ring A is

R₃ is H; R₃′ is H; R₄ is H or cyano; and R₅ is H or cyano; or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1,wherein L is a bond, —O—, —SO₂—NH—, —NH—SO₂—, —SO₂—, —S—, or —C(═O)—; R₁is H or CF₃; R₂ is H, methyl, ethyl, propyl, isopropyl, tert-butyl,cyclopropyl, cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl,morpholin-4-yl, thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, orpyrimidin-4-yl, provided R₂ is not H if L is a bond, and wherein R₂ isoptionally substituted with hydroxyl, fluoro, amino, oxo, methyl, or—CH₂—NH₂; V is CH or N; W is CR″ or N, wherein R″ is H or F; ring A is

R₃ is H; and R₃′ is H; or a pharmaceutically acceptable salt thereof. 4.The compound of claim 1, wherein the compound is selected from:5-(3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,6-Amino-3-[3-fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazine-2-carbonitrile,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide(racemic),4′-(5-Aminopyrazin-2-yl)-N-(cyclobutylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(endo)-4′-(5-Aminopyrazin-2-yl)-N-bicyclo[2.2.1]hept-2-yl-3′-fluorobiphenyl-2-sulfonamide(racemic),4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1-methylcyclobutyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(1,1-dimethylpropyl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopentyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-phenylethyl)biphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2,3-dihydro-1H-inden-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-phenylethyl]biphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-N-[(3S)-1-ethyl-2-oxoazepan-3-yl]-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3S)-1-methyl-2-oxoazepan-3-yl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-pyridin-3-ylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfamide,N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)propane-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]propane-1-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-2-methylpropane-1-sulfonamide,N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclopropanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]hexane-1-sulfonamide,N-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)cyclobutanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1,1,1-trifluoromethanesulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide,5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(4,4-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoropiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(3,3-Difluoroazetidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[2′-(Azepan-1-ylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(trifluoromethyl)piperidin-4-ol,5-(3-Fluoro-2′-{[4-(methylsulfonyl)piperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,5-{2′-[(4-Acetylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(2′-{[4-(Cyclopropylcarbonyl)piperazin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,2-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanol,5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(3,5-Dimethylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-3-carbonitrile,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carbonitrile,5-{2′-[(4-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-one,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-ol,(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)methanol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)ethanol,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol,2-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol,5-(3-Fluoro-2′-{[4-(methylamino)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,5-(2′-{[4-(Dimethylamino)piperidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,N-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide,(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)methanol,tert-Butyl(1-{[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)carbamate,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxypropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2R)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,(R)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(S)-5-(2′-((3-aminopyrrolidin-1-yl)sulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-(2′-{[2-(Aminomethyl)pyrrolidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,(S)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(methylsulfonyl)biphenyl-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxypropyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1-hydroxycyclohexyl)methyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-1,1-dimethylpropyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-N-(2,3-dihydroxypropyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(trans)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3,4-diol,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-sulfonamide,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)pyrrolidin-3-yl)methanol,(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-yl)methanol,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-oxopiperidin-3-yl)biphenyl-2-sulfonamide,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide,(S)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-N-piperidin-3-ylbiphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-phenylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxy-2-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-ol,(trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxycyclohexyl)biphenyl-2-sulfonamide,(trans)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide,(cis)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-(hydroxymethyl)cyclohexyl]biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-piperidin-4-ylbiphenyl-2-sulfonamide,5-(2′-{[3-(Aminomethyl)azetidin-1-yl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-(azetidin-3-ylmethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-5-(3-Fluoro-2′-{[3-(methylamino)pyrrolidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,(R)-4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide,5-[3-Fluoro-2′-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one,5-(2′-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-(2′-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-hydroxypentyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(6-hydroxyhexyl)biphenyl-2-sulfonamide,N-(4-Aminocyclohexyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-(1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2,3-dihydro-1H-indol-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,(S)-5-{2′-[(3-Aminopiperidin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N,N-bis(2-hydroxyethyl)biphenyl-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidine-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N-cyclopropyl-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide,(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol,(1R,5 5)-34(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-azabicyclo[3.1.0]hexan-6-amine,(S)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(R)-5-(3-fluoro-2′-((2-methylpiperazin-1-yl)sulfonyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,(R)-(1-((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperazin-2-yl)methanol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3-methylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,tert-Butyl[2-({[4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]carbamate,N-(2-Aminoethyl)-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-hydroxybutan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(pyrrolidin-3-yl)-[1,1′-biphenyl]-2-sulfonamide,N-[2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}amino)ethyl]acetamide,(S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)propanoicacid,4′-(5-Aminopyrazin-2-yl)-N-[2-(carbamoylamino)ethyl]-3′-fluorobiphenyl-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[6-(trifluoromethyl)pyridin-3-yl]biphenyl-2-sulfonamide,5-(3-Fluoro-2′-{[4-(1H-imidazol-4-yl)piperidin-1-yl]sulfonyl}biphenyl-4-yl)pyrazin-2-amine,N-[(4-Amino-2-methylpyrimidin-5-yl)methyl]-4′-(5-aminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2,6-dimethoxypyrimidin-4-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(5-methylpyrazin-2-yl)biphenyl-2-sulfonamide,(S)-2-(4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)-4-methylpentanamide,4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide,(R)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(5-aminopyrazin-2-yl)-N-(1-cyanopropan-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(3-methyloxetan-3-yl)biphenyl-2-sulfonamide,3-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)propanenitrile,(S)-4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(1-methoxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,5-{3-Fluoro-2′-[(4-pyrazin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(4-pyrimidin-2-ylpiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-(2′-Amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3-phenylpyrrolidin-3-ol,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide,N′-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide,(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol,(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-3-ol,(3′S,4′S)-1′-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-1,3′-bipyrrolidin-4′-ol,(3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-morpholin-4-ylpyrrolidin-3-ol,(3S,4S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(4-methylpiperazin-1-yl)pyrrolidin-3-ol,5-{3-Fluoro-2′-[(trifluoromethyl)-sulfanyl]biphenyl-4-yl}pyrazin-2-amine,5-[2′-(tert-Butylsulfanyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Ethylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(propylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(2-methylpropyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclopentylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclobutylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-{3-Fluoro-2′-[(1-methylethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(trifluoromethyl)sulfonyl]biphenyl-4-yl}pyrazin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}acetamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}-N,N-diethylacetamide,5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfanyl]biphenyl-4-yl}pyrazin-2-amine,(racemic)5-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}methyl)-1,3-oxazolidin-2-one,N-(2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}ethyl)benzamide,5-(3-Fluoro-2′-{[4-(methylsulfonyl)benzyl]sulfanyl}biphenyl-4-yl)pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-[3-Fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one,4′-(5-aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride,5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-amineformate salt,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-4-aminehydrochloride,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride,5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-5-aminehydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonamideformic acid salt,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(2-hydroxyethyl)methanesulfonamideformic acid salt,1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)azetidin-3-olformic acid salt,4-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperazin-2-oneformic acid salt,(S)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)methanesulfonamide,(R)-1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)-N-(1-hydroxypropan-2-yl)methanesulfonamidehydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-(trans-4-hydroxycyclohexyl)methanesulfonamide,(S)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamidehydrochloride,(R)-1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-[(2S)-2-hydroxypropyl]methanesulfonamide,5-(2′-{[(4-Aminopiperidin-1-yl)sulfonyl]methyl}-3-fluorobiphenyl-4-yl)pyrazin-2-aminehydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamidehydrochloride,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamideformate salt,1-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]ureahydrochloride,N-[1-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfonyl)piperidin-4-yl]acetamideformate salt,5-{2′-[(Ethylsulfanyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amineformate salt,5-{3-Fluoro-2′-[(methylsulfanyl)methyl]biphenyl-4-yl}pyrazin-2-aminehydrochloride,5-(3-Fluoro-2′-{[(1-methylethyl)sulfanyl]methyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride,2-(((4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-aminehydrochloride,6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyrimidin-4-aminehydrochloride,5-(3-fluoro-2′-((pyridazin-3-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride,6-(((4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methyl)thio)pyridazin-3-aminehydrochloride,5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-aminehydrochloride,5-(3-fluoro-2′-((pyrimidin-4-ylthio)methyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrazin-2-aminehydrochloride,5-(3-Fluoro-2′-{[3-(methylsulfonyl)propyl]sulfonyl}biphenyl-4-yl)pyrazin-2-aminehydrochloride,5-(3-Fluoro-2′-{[(2R)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)propyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-(2-cyanoethyl)-3′-fluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}morpholin-2-yl)methanol,5-(3-Fluoro-2′-{[(2S)-2-methylpiperazin-1-yl]sulfonyl}biphenyl-4-yl)pyrimidin-2-amine,5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]biphenyl-2-sulfonamide,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3S)-piperidin-3-yl]biphenyl-2-sulfonamide,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-N-[(3R)-piperidin-3-yl]biphenyl-2-sulfonamide,[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-yl]methanol,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(cis)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(trans)-2-hydroxycyclohexyl]biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-N-(1-methylethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(trans-4-hydroxycyclohexyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]biphenyl-2-sulfonamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}azetidin-3-oltrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3R)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(3S)-2-oxopiperidin-3-yl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-2-methylpropyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-[(2S)-2,3-dihydroxypropyl]-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,[(2R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanoltrifluoroacetic acid salt,[(2S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidin-2-yl]methanoltrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,5-{2′-[(4-Cyclopropylpiperazin-1-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminetrifluoroacetic acid salt,2-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-1-yl)ethanoltrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-(cyclopropylmethyl)-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid,4′-(2-Aminopyrimidin-5-yl)-N-cyclopropyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-phenylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-3′-fluoro-3-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(piperazin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-phenylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[2′-(tert-Butylsulfonyl)-3-fluorobiphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-methylpropyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2,2,2-trifluoro-1,1-dimethylethyl)biphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N,N-dimethylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,5-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrimidin-2-aminetrifluoroacetic acid salt,4′-(2-aminopyrimidin-5-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetic acid salt,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperazin-2-onetrifluoroacetic acid salt, tert-ButylN-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate,N-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alanine,N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]pyrrolidine-1-sulfonamide,N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]morpholine-4-sulfonamide,N′-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]-N,N-dimethylsulfamide,5-(2′-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyrimidin-2-amine,6-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-2-thia-6-azaspiro[3.3]heptane2,2-dioxide,1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)azetidine-3-carbonitrile,1-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-(trifluoromethyl)azetidin-3-ol,5-{2′-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride,2-(((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)methyl)quinazolin-4(3H)-one,1-(3-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one,5-(2′-{[3-(Cyclohexylsulfonyl)propyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,5-{3-Fluoro-2′-[(1-methyl-1H-benzimidazol-2-yl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine,5-(2′-{[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-[3-fluoro-2′-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,4-{[4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]sulfonyl}piperazin-2-one,4′-(2-aminopyrimidin-5-yl)-3′-fluoro-N-methyl-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{3-Fluoro-2′-[(4-methylpiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(5-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(4-Aminopyrimidin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(5-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-(pyrazin-2-ylsulfanyl)biphenyl-4-yl]pyrimidin-2-aminehydrochloride,5-{2′-[(6-Aminopyrimidin-4-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrimidin-2-amineformate salt,5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amineformate salt,5-{2′-[(5-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfonyl)biphenyl-4-yl]pyrimidin-2-amineformate salt,5-{2′-[(5-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-aminehydrochloride,5-[3-Fluoro-2′-({[2-(trimethylsilyl)ethoxy]methyl}sulfanyl)biphenyl-4-yl]pyrimidin-2-amine,5-(3-Fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-N,N-diethyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,5-(3-fluoro-2′-(pyrrolidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,5-(3-fluoro-2′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-aminopyridin-3-yl)-N-cyclohexyl-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-isobutyl-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(tert-pentyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(2,2,2-trifluoro-1-phenylethyl)-[1,1′-biphenyl]-2-sulfonamide,(R)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1-methylcyclobutyl)-[1,1′-biphenyl]-2-sulfonamide,4-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine1,1-dioxide,(S)-4′-(6-aminopyridin-3-yl)-3′-fluoro-N-(1,1,1-trifluoropropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,5-(2′-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine,tert-butyl3-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-ylsulfonamido)methyl)-3-hydroxyazetidine-1-carboxylate,4′-(6-aminopyridin-3-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide,2-(1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)ethanol,1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-ol,(1-((4′-(6-aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)methanol,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]pyridin-3-yl}phenyl)pyrazin-2-amine,5-{2-Fluoro-4-[2-(1-methylethoxyl)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{4-[2-(Cyclopentyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,5-{4-[2-(Cyclohexyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,5-[2-Fluoro-4-(2-methoxypyridin-3-yl)phenyl]pyrazin-2-amine,5-{4-[2-(Cyclobutyloxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,tert-Butyl3-[({3-[4-(5-aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)methyl]pyrrolidine-1-carboxylate,5-{2-Fluoro-4-[2-(pyrrolidin-3-ylmethoxy)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2-Fluoro-4-[2-(1-methylethoxyl)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-[4-(2-Aminopyridin-3-yl)-2-fluorophenyl]pyrimidin-2-amine,4′-(5-amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,3-Amino-6-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,3-Amino-6-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]biphenyl-4-yl}pyrazine-2-carbonitrile,4′-(5-Amino-6-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,3-Amino-6-[3-fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazine-2-carbonitrile,4′-(6-Aminopyridazin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-4′-(5,6-diaminopyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,4′-(6-Amino-5-fluoropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-methoxypyrazine-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(6-Amino-4-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(6-amino-2-cyanopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Amino-6-chloropyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-bromopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,6-amino-3-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)picolinonitrile,4′-(5-Amino-6-methylpyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,4′-(5-Amino-6-methylpyrazin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,N-tert-Butyl-4′-(5,6-diaminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide,4′45-Amino-6-methylpyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,4′-(6-Amino-5-cyanopyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(6-Amino-5-chloropyridin-3-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-[6-Amino-5-(trifluoromethyl)pyridin-3-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-[2-Amino-4-(trifluoromethyl)pyrimidin-5-yl]-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Amino-4-methylpyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]acetamide,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]urea,5-[2,3-Difluoro-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methylbiphenyl-2-yl]methanesulfonamide,4′-(5-Aminopyrazin-2-yl)-2′,3′-difluorobiphenyl-2-sulfonamide,4′-(2-Aminopyrimidin-5-yl)-2′,3′-difluoro-N-methylbiphenyl-2-sulfonamidetrifluoroacetic acid salt,4′-(2-Aminopyrimidin-5-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamidetrifluoroacetic acid salt,5-[2′,3-Difluoro-4′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine,5-(2′,3-Difluorobiphenyl-4-yl)pyrazin-2-amine,5-(2′-Chloro-3-fluorobiphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-methylbiphenyl-4-yl)pyrazin-2-amine,5-[2′,3-Difluoro-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-(3-Fluoro-2′-methoxybiphenyl-4-yl)pyrazin-2-amine,5-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(trifluoromethoxy)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-ol,5-[3-Fluoro-2′-(phenylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-(2′,3,6′-Trifluorobiphenyl-4-yl)pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]benzenesulfonamide,5-(2′-Ethyl-3-fluorobiphenyl-4-yl)pyrazin-2-amine,{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid,5-[3-Fluoro-2′-(1-methylethyl)biphenyl-4-yl]pyrazin-2-amine,1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]ethanone,5-[3-Fluoro-2′-(2,2,2-trifluoroethoxy)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxylic acid,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carboxamide,5-[3-Fluoro-2′-(1-methylethoxyl)biphenyl-4-yl]pyrazin-2-amine,5-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonmide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-ethylmethanesulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N,2-dimethylpropane-1-sulfonamide,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrimidin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-N,N-diethyl-3′-fluorobiphenyl-2-carboxamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,5-[3-Fluoro-2′-(piperazin-1-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(4-Acetylpiperazin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-cyclohexyl-3′-fluorobiphenyl-2-carboxamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-methylbiphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-4-ol,5-{2′-[(4-Aminopiperidin-1-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-carboxamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]biphenyl-2-carboxamide,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperazin-2-one,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-2-carbonitrile,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}methyl)pyridine-3-carbonitrile,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-4-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(2-methylpyrimidin-4-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(4-methylpyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(5-methoxypyrimidin-2-yl)oxy]biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-methoxy-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol,4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-4-amine,5-[3-Fluoro-4′-(trifluoromethyl)-2′-{[2-(trimethylsilyl)ethoxy]methoxy}biphenyl-4-yl]pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol,5-{2′-[(4-Aminopyrimidin-2-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]oxy}pyrimidin-2-amine,5-{2′-[(6-Aminopyrimidin-4-yl)oxy]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrimidin-2-amine,5-[3-Fluoro-2′,4′-bis(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbonitrile,5-{5-[2-(Pyrimidin-2-yloxy)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-5-(trifluoromethyl)phenoxy}pyrimidin-2-amine,5-{5-[2-(Pyrimidin-2-yloxy)phenyl]pyridin-2-yl}pyrimidin-2-amine,4-{2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenoxy}pyrimidin-2-amine,5-(5-{2-[(4-Aminopyrimidin-2-yl)oxy]phenyl}pyridin-2-yl)pyrimidin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-methoxybiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N-tert-butylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-N,N-dimethylbiphenyl-2-sulfonamide,5-[2′-(Morpholin-4-ylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-2′-fluorobiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-2′-fluoro-N,N-dimethylbiphenyl-2-sulfonamide,5-[2′-(Methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N,N,3′-trimethylbiphenyl-2-sulfonamide,4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)biphenyl-2-yl]methanesulfonamide,4′-(5-Aminopyrazin-2-yl)biphenyl-2-sulfonamide,3-Amino-6-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylicacid,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N-diethylacetamide,5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine,5,5′-(3,3″-Difluoro-1,1′:2′,1″-terphenyl-4,4″-diyl)dipyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde,5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol,5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine,5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine,5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-2-methylpyrimidin-4-amine,5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol,5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrimidin-2-amine,5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine,{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile,{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile,{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid,5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine,2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol,2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol,5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine,5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amineformic acid salt,5-{2-Fluoro-4-[2tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine,(2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,(2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,(2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,(2I)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,N(4′-((6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)methanesulfonamide,5-(3-Fluoro-2′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide,4′-(6-Aminopyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamidetrifluoroacetate,5-(2′-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-ylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)pyridin-2-amine,4′-(6-Aminopyrazin-2-yl)-3′-fluoro-N-((3-hydroxyazetidin-3-yl)methyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-((1S,25)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide,4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(1-hydroxy-2-methylpropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,(racemic)-1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-ol,4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide,N-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-4-yl)acetamide,2-(1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)ethanol,1-((4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidin-3-yl)methanol,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide,5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,5-{5-[2-(Morpholin-4-ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin-2-amine,5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt,5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt,5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt,5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-aminetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethylbenzenesulfonamidetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamidetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamidetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamidetrifluoroacetic acid salt,4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulfonyl)piperazin-2-one,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide,5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-aminetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamidetrifluoroacetic acid salt,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide,3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitriletrifluoroacetic acid salt,5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin-2-amine,5-(3-fluoro-2-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-(2′,3,4′-Trifluorobiphenyl-4-yl)pyrazin-2-amine, racemic5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carbonitrile,1-(4′-(5-Aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)imidazolidin-2-on,4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,6-Amino-3-{2′-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,1-((4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)piperidine-4-carboxamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)-[1,1′-biphenyl]-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,6-Amino-3-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2-carbonitrile,N-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3-dimethylbutan-2-one,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine;5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine,5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine,5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine,5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide,5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide,5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide,5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine,5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(3-Fluoro-2′-(pyrimidin-4-ylthio)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine,5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile,6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2-carbonitrile,6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrile,N-(tert-Butyl)-3′-fluoro-4′-(5-(methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide,5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-aminehydrogen chloride salt,5-{3-Fluoro-2′-[(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine,5-(3-Fluoro-2′-{[(1-methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine,5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin-4-amine,racemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-carboxamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(diastereomeric mixture),1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol(diastereomeric mixture),4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide,(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,(cis/trans)4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide,(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,(cis/trans)4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide,racemic5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine;(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol;(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol;(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol;(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol;(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol;(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol;5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine(diastereoisomeric mixture),5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine;5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine;5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine;5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine;5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine;5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine;5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine(diastereoisomeric mixture),5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine;5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2-amine;2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide;2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide;2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-5-(trifluoromethyl)benzamide;2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-(3-hydroxyazetidin-1-yl)methanone;[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[4-(methylamino)-1-piperidyl]methanone;[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone;2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tert-butyl-5-(trifluoromethyl)benzamide;[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone;[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-5-(trifluoromethyl)phenyl]-(4-hydroxy-1-piperidyl)methanone;2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]-N-tetrahydropyran-4-yl-benzamide[2-[4-(5-Aminopyrazin-2-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone;racemic[2-[4-(2-Aminopyrimidin-5-yl)-3-fluoro-phenyl]phenyl]-[2-(hydroxymethyl)morpholin-4-yl]methanone;N-{3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide;N-{3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamideracemic5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrazin-2-aminehydrochloride;5-(2-Fluoro-4-(2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl)phenyl)pyrimidin-2-amineformic acid salt,5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride,5-(4-(2-(Cyclobutylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride;5-(4-(2-(Cyclohexlsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-aminehydrochloride;5-(4-(2-(Cyclohexylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride;5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidine-2-aminehydrochloride;5-(4-(2-(Cyclopentylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-aminehydrochloride;5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformic acid salt,5-(4-(2-(tert-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformic acid salt, racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrimidin-2-amineformate; racemic5-(4-(2-(sec-Butylsulfonyl)pyridin-3-yl)-2-fluorophenyl)pyrazin-2-amineformate;1-((3-(4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanone;1-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)piperidin-1-yl)ethanonehydrogen chloride salt;5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-aminehydrogen chloride salt,5-(2-Fluoro-4-(2-((3-methoxypropyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-aminehydrogen chloride salt,4-((3-(4-(2-aminopyrimidin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide;4-((3-(4-(2-Aminopyrazin-5-yl)-3-fluorophenyl)pyridine-2-yl)sulfonyl)tetrahydro-2H-thiopyran1,1-dioxide;5-(2-Fluoro-4-(2-((2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrimidin-2-amineformic acid salt,5-(2-Fluoro-4-(2-(2-morpholinoethyl)sulfonyl)pyridine-3-yl)phenyl)pyrazin-2-amine;5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrimidin-2-amineformic acid salt,5-(2-Fluoro-4-(2-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)pyridine-3-yl)pyrazin-2-amineformic acid salt,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine;5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amineformic acid salt,5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amineformic acid salt,5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amineformic acid salt,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride;5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amineformic acid salt,5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-aminehydrochloride; 5-(2,3-Difluorobiphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2-methoxybiphenyl-4-yl)pyrazin-2-amine,5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2′-methoxybiphenyl-2-sulfonamide,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide,5-(3-Fluoro-2′-(pyrazin-2-yl)-[1,1′-biphenyl]-4-yl)pyrazin-2-amine;5-(3-Fluoro-2′-pyrazin-2-ylbiphenyl-4-yl)pyrimidin-2-amine,5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrazin-2-amine,5-[2′45-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine,5-[2′-(6-Aminopyrazin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidin-2-amine,5,5′-(3′-Fluorobiphenyl-2,4′-diyl)dipyrimidin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine,5-[3-Fluoro-2′-(1-methyl-1H-pyrazol-4-yl)biphenyl-4-yl]pyrazin-2-amine,5-(3-Fluoro-2′-pyrimidin-5-ylbiphenyl-4-yl)pyrazin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrimidine-2-carbonitrile,5-[3-Fluoro-2′-(2-morpholin-4-ylpyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine,1-{4-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-1H-pyrazol-1-yl}-2-methylpropan-2-ol,5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine,5-{2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]phenyl}pyrimidin-2-amine,5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine,5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine;5-[2′-(1,1-Dioxido-1,2-thiazinan-2-yl)-3-fluorobiphenyl-4-yl]pyrazin-2-amine;5-[2′-(1,1-Dioxidoisothiazolidin-2-yl)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine;5-[2-Fluoro-4-(2-pyrrolidin-1-ylpyridin-3-yl)phenyl]pyrazin-2-amine;1-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]pyrrolidin-2-one;5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H-pyrrolo[2,3-b]pyridine;5-(2′,3,4′-Trifluorobiphenyl-4-yl)pyrazin-2-amine;5-[3-Fluoro-2′-(methylsulfinyl)biphenyl-4-yl]pyrazin-2-amine;5-[2′-(Methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine;5-[3-Methyl-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine;4′-(5-Aminopyrazin-2-yl)-3′-hydroxybiphenyl-2-sulfonamide;N-[4′-(5-Aminopyrazin-2-yl)biphenyl-2-yl]methanesulfonamide;4′45-Aminopyrazin-2-yl)biphenyl-2-sulfonamide;4′-(6-Aminopyridazin-3-yl)-3′-fluorobiphenyl-2-sulfonamide;N-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2-sulfonamide;3-Amino-6-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carboxylicacid;4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-(trifluoromethyl)biphenyl-2-sulfonamide,5-{5-[2-(Cyclopropylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}acetamide,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N,N-diethylacetamide,5-{3-Fluoro-2′-[(2-morpholin-4-yl-2-oxoethyl)sulfonyl]biphenyl-4-yl}pyrimidin-2-amine,5-[5-(2-Methoxyphenyl)pyridin-2-yl]pyrimidin-2-amine,5-{5-[2-(Morpholin-4-ylcarbonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,4′-(2-Amino-4-cyanopyrimidin-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,5-[3-Fluoro-2′-(pyrimidin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine,5-[3-Fluoro-2′-(pyrazin-2-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine,N-(2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}ethyl)benzamide,5-[3-Fluoro-2′-(pyrimidin-4-ylsulfonyl)biphenyl-4-yl]pyrimidin-2-amine,5-{2′-[(6-Aminopyrimidin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(4-Aminopyrimidin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(5-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-(2-Fluoro-4-{2-[(2-morpholin-4-ylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine,5-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-5-(trifluoromethyl)biphenyl-2-yl]pyrimidin-2-amine,5-{5-[2-(2-Aminopyrimidin-5-yl)phenyl]pyridin-2-yl}pyrimidin-2-amine,4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-2-amine,5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine,5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine,(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol,(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol,(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol,2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol,5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrimidin-2-amine;2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine,5-(2′-{[1-(Aminomethyl)cyclopentyl]sulfonyl}-3-fluorobiphenyl-4-yl)pyrimidin-2-amine,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide,(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetic acid,4′-(2-Aminopyrimidin-5-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-carboxamide;4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(tetrahydro-2H-pyran-4-yl)biphenyl-2-carboxamide,5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrazin-2-amine,5-[2′-(2-Aminoethoxy)-3-fluorobiphenyl-4-yl]pyrimidin-2-amine,2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,N-[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,4′-(5-Aminopyrazin-2-yl)-N,N,3′-trimethylbiphenyl-2-sulfonamide,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-sulfonamide,4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine,5-[3-Fluoro-2′-(piperidin-4-yloxy)biphenyl-4-yl]pyrazin-2-amine,N-[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-2′-methoxybiphenyl-2-yl]methanesulfonamide,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}azetidin-3-ol,(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}pyrrolidin-3-ol,4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-carbonitrile,(2R)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,5-{2-Fluoro-4-[2-(piperidin-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2′-[(6-Aminopyrazin-2-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,4′-(6-Aminopyridin-3-yl)-3′-fluorobiphenyl-2-sulfonamide;5-{3-Fluoro-2′-[(methylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine,5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrimidin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-(4-hydroxycyclohexyl)biphenyl-2-carboxamide,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-3,3-dimethylbutan-2-one,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol,2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)ethanol,5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,N-[4′-(6-Aminopyridin-3-yl)-3′-fluorobiphenyl-2-yl]methanesulfonamide,4-({2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]phenyl}sulfonyl)piperazin-2-one,5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2S)-2-hydroxypropyl]benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide,5-{2-Fluoro-4-[2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-(5-{2-[(3,3-Difluoropyrrolidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethylbenzenesulfonamide,(3S)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,(2S)-2-({3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,2-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile,(2R)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrimidin-4-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-5-methoxybiphenyl-2-sulfonamide,5-(2-Fluoro-4-{2-[(3-methoxypropyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide,5-[3-Fluoro-2-methoxy-2′-(methylsulfonyl)biphenyl-4-yl]pyrazin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}ethanol,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanamide,{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile,5-{4-[2-(tert-Butylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(3S)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine,5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine,5-(2-Fluoro-4-{2-[(2-morpholin-4-ylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine,5-(4-{2-[(1-Acetylpiperidin-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine,5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)pyrazin-2-amine,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2′-[(Ethylsulfonyl)methyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile,(3S)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3-carboxamide,5-{5-[2-(Morpholin-4-ylmethyl)-4-(trifluoromethyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,5-(5-{2-[(4,4-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine,5-{2′-[(2,6-Dimethylmorpholin-4-yl)carbonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,(3R)-1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}pyrrolidine-3-carboxamide,5-(2-Fluoro-4-{2-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide,(3R)-1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}piperidin-3-ol,5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]pyrazin-2-amine,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol,5-{3-Fluoro-2′-[(pyrimidin-2-ylsulfonyl)methyl]biphenyl-4-yl}pyrazin-2-amine,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-[(2R)-2-hydroxypropyl]benzenesulfonamide,5-(5-{2-[(3,3-Difluoropiperidin-1-yl)sulfonyl]phenyl}pyridin-2-yl)pyrimidin-2-amine,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine,5-[3-Fluoro-2′-(1,2,3,6-tetrahydropyridin-4-yl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine,5-{2-Fluoro-4-[2-(pyrrolidin-3-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine,6-Amino-3-{2′-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile,N-(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-yl)acetamide,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-N-methylazetidine-3-carboxamide,5-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]pyridin-2-amine,5-(3-Fluoro-2′-{[(1-methylethyl)sulfonyl]methyl}biphenyl-4-yl)pyrazin-2-amine,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)biphenyl-2-sulfonamide,{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}acetonitrile,(2S)-2-({3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}oxy)propan-1-ol,6-Amino-3-[2′-(cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]pyrazine-2-carbonitrile,5-(4-{2-[(trans-4-Aminocyclohexyl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzenesulfonamide,5-{5-[2-(Azepan-1-ylsulfonyl)phenyl]pyridin-2-yl}pyrimidin-2-amine,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-tert-butylbenzenesulfonamide,2-[6-(2-Aminopyrimidin-5-yl)pyridin-3-yl]-N-(dicyclopropylmethyl)benzenesulfonamide,5-{2′-[(4-Aminopiperidin-1-yl)methyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,5-{2′-[(6-Amino-2-methylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine,5-(2-Fluoro-4-{2-[(1-methylpropyl)sulfonyl]pyridin-3-yl}phenyl)pyrimidin-2-amine;4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2S)-2-hydroxypropyl]biphenyl-2-sulfonamide,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-2-methylpropanenitrile,5-{4-[2-(Cyclobutylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine,5-{2′-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{2′-[(Cyclopropylmethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylicacid,5-(3-Fluoro-2′-{[2-(trifluoromethyl)pyridin-4-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-(2-Fluoro-4-{2-[(3-methoxypropyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]pyrazine-2-carbonitrile,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-2′-methoxybiphenyl-2-sulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(2R)-2-hydroxypropyl]biphenyl-2-sulfonamide,1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-ol,5-(4-{2-[(1-Acetylpiperidin-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine,5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}pyrazin-2-amine,2-(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)ethanol,5-{2′-[(5-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarboxamide,6-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,5-(3-Fluoro-2′-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,(1-{[4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-3-yl)methanol,6-Amino-3-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile,5-[3-Fluoro-2′-(2-methoxypyrimidin-5-yl)biphenyl-4-yl]pyrazin-2-amine,5-(2-Fluoro-4-{2-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,5-{4-[2-(tert-Butylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,3-Amino-6-{2′-[(4-aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazine-2-carbonitrile,6-Amino-3-{3-fluoro-2′-[(3-oxopiperazin-1-yl)sulfonyl]-4′-(trifluoromethyl)biphenyl-4-yl}pyrazine-2-carbonitrile,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxamide,5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrazin-2-amine,5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,1-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}cyclopentanecarbonitrile,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-3-carbonitrile,4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide,5-{4-[2-(Cyclohexylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine,5-{3-Fluoro-2′-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]sulfonyl}biphenyl-4-yl}pyrazin-2-amine,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidine-4-carboxamide,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carbaldehyde,4′-(5-Aminopyrazin-2-yl)-3′-fluoro-N-[(3-hydroxyazetidin-3-yl)methyl]biphenyl-2-sulfonamide,5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]sulfanyl}pyrazin-2-amine,5-{2′-[(6-Cyclopropylpyrimidin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,2-({[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]methyl}sulfanyl)pyrimidin-4-amine,4′-(6-Amino-5-fluoropyridin-3-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbiphenyl-2-sulfonamide,5-{4-[2-(Cyclopentylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrimidin-2-amine,2-[3-Fluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,6-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyridine-2-carbonitrile,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)sulfonyl]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine,5-{4-[2-(Cyclopropylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbiphenyl-2-sulfonamide,5-{2′-[(1,1-Dioxidothiomorpholin-4-yl)carbonyl]-3-fluoro-4′-(trifluoromethyl)biphenyl-4-yl}pyrazin-2-amine,N,N-Diethyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,5-{2-Fluoro-4-[2-(tetrahydro-2H-pyran-4-ylsulfonyl)pyridin-3-yl]phenyl}pyrazin-2-amine,5-{2′-[(6-Aminopyrazin-2-yl)sulfanyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(2-Fluoro-4-{2-[(1-methylpropyl)sulfonyl]pyridin-3-yl}phenyl)pyrazin-2-amine,4′-(6-Aminopyridin-3-yl)-3′-fluoro-N-(2-hydroxy-1,1-dimethylethyl)biphenyl-2-sulfonamide,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-ethyl-5-(trifluoromethyl)benzenesulfonamide,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(3-hydroxy-2,2-dimethylpropyl)biphenyl-2-sulfonamide,6-Amino-3-[3-fluoro-2′-(pyrimidin-2-yloxy)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazine-2-carbonitrile,5-[3-Fluoro-2′-(morpholin-4-ylmethyl)-4′-(trifluoromethyl)biphenyl-4-yl]pyrazin-2-amine,4′-(5-Amino-3-cyanopyrazin-2-yl)-3′-fluoro-N-(2-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-{2′-[(5-Aminopyridin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-{4-[2-(Cyclobutylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine;4′-(5-Amino-3-cyanopyrazin-2-yl)-N-ethyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide,5-[3-Fluoro-2′-(pyrimidin-4-ylsulfanyl)biphenyl-4-yl]pyrazin-2-amine,1-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-4-(pentafluoroethyl)piperidin-4-ol,5-{2′-[(2-Aminopyridin-4-yl)oxy]-3-fluorobiphenyl-4-yl}pyrazin-2-amine,5-(2-Fluoro-4-{2-[(1-methylethyl)sulfonyl]pyridin-3-yl}phenyl)-1H-pyrrolo[2,3-b]pyridine,2-[6-(2-Aminopyrimidin-5-yl)-5-fluoropyridin-3-yl]-N-tert-butylbenzenesulfonamide,tert-Butyl(1-{[3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-yl)carbamate,5-{4-[2-(Cyclopentylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3,3′-difluorobiphenyl-2-sulfonamide,5-{4-[2-(Cyclohexylsulfonyl)pyridin-3-yl]-2-fluorophenyl}pyrazin-2-amine,4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′,4-difluorobiphenyl-2-sulfonamide,5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrimidin-2-amine,5-(3-Fluoro-2′-{[(2S)-2-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}pyrimidin-5-amine,5-{2′-[(5-Aminopyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-(2-fluoro-4-(2-(piperidin-4-yloxy)pyridin-3-yl)phenyl)pyrazin-2-amine,5-{2-Fluoro-4-[2-(piperidin-4-yloxy)pyridin-3-yl]phenyl}pyrimidin-2-amine,2-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]oxy}-6-methylpyrimidin-4-amine,5-{2′-[(4-Amino-6-methylpyrimidin-2-yl)oxy]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,5-(3-Fluoro-2′-{[(3R)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrazin-2-amine,5-(3-Fluoro-2′-{[(3S)-3-methylmorpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine,5-(4-{2-[(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy]pyridin-3-yl}-2-fluorophenyl)pyrimidin-2-amine;5-(3-Fluoro-2′-{[6-(trifluoromethyl)pyridin-2-yl]oxy}biphenyl-4-yl)pyrimidin-2-amine,5-{3-Fluoro-2′-[(3R)-piperidin-3-yloxy]biphenyl-4-yl}pyrazin-2-amine,1-(4-{[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol,1-(4-{[4′-(2-Aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]carbonyl}morpholin-2-yl)ethanol,5-(3-Fluoro-2′-{[2-(trifluoromethyl)morpholin-4-yl]carbonyl}biphenyl-4-yl)pyrazin-2-amine,N-{3-[4-(5-Aminopyrazin-2-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide,N-{3-[4-(2-Aminopyrimidin-5-yl)-3-fluorophenyl]pyridin-2-yl}-2,2-dimethylpropanamide,5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrazin-2-amine;5-{2′-[(2-Amino-1,1-dimethylethyl)sulfonyl]-3-fluorobiphenyl-4-yl}pyrimidin-2-amine,N-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2-dimethylpropanamide,and4′-(5-Aminopyrazin-2-yl)-N-tert-butyl-3′-fluoro-4-(trifluoromethyl)biphenyl-2-sulfonamide.5. A pharmaceutical composition comprising at least one compound ofclaim 1 and at least one pharmaceutically acceptable carrier.
 6. Thepharmaceutical composition of claim 5 comprising at least one compoundof claim
 4. 7. A process for making a pharmaceutical compositioncomprising admixing any of the compounds according to claim 1 and apharmaceutically acceptable carrier.